Incidence of Fatigue Following Dexamethasone Administration for Supportive Therapy and Efficacy of Tapering in Perioperative Chemotherapy for Breast Cancer: A Retrospective Observational Study.

In perioperative chemotherapy for breast cancer, dexamethasone (DEX) is administered at high dose to prevent adverse effects. Abrupt cessation of high-dose DEX treatment induces fatigue, but the incidence of the fatigue is uncertain. In this study, we retrospectively evaluated the incidence of fatigue following DEX administration for supportive therapy and the improvement of fatigue with DEX tapering, a gradual reduction of the daily dose, in breast cancer patients. The subjects were 124 patients with breast cancer receiving epirubicin- or docetaxel-based regimens as perioperative chemotherapy. Of all patients, 16.1% of patients experienced fatigue after cessation of DEX administration. The severity of fatigue was grade 1 in 6.5% of patients, grade 2 in 8.1% of patients, and grade 3 in 1.6% of patients. There were no significant differences in dose and duration of DEX administration between the group with fatigue and the group without fatigue. In almost all patients with fatigue, DEX tapering was performed from the next cycle. The efficacy of DEX tapering was evaluated by comparing the grade and subjective symptoms. Following DEX tapering, the severity of fatigue was significantly reduced (p < 0.05), and the subjective symptom was improved in 94.7% of patients. Therefore, fatigue is occasionally induced after the cessation of DEX administration for supportive therapy in breast cancer patients. The tapering of DEX may be effective for fatigue.

Differences in Biologic Drug Effects and Distal Particulate Embolization in Three Paclitaxel-Coated Balloons for Femoropopliteal Lesions in a Rabbit Model.

BACKGROUND: A recent meta-analysis of randomized control trials demonstrated a significantly higher risk of major amputation in patients treated with drug-coated balloons (DCBs) compared with standard treatment, especially in high-dose paclitaxel-coated DCBs. Distal particulate embolization after DCB use was considered a potential cause of the higher incidence of major amputation. The current study aimed to histologically and biologically compare biologic drug effect and distal particulate embolization in 3 DCBs (a high-dose paclitaxel-coated DCB [IN.PACT Admiral] and 2 low-dose paclitaxel-coated DCBs [Ranger and Lutonix]). METHODS AND RESULTS: The DCBs were inflated in the healthy descending aortas of 18 rabbits, followed by euthanasia 28 days after the procedure. The treated descending aorta and distal skeletal muscles were histopathologically evaluated, and paclitaxel concentrations were measured. The paclitaxel concentration of the treated lesion was highest for Ranger, followed by IN.PACT and Lutonix (Ranger vs IN.PACT vs Lutonix: 1089 [745-2170] pmol/mg vs 638 [160-2075] pmol/mg vs 25 [10-304] pmol/mg, respectively; p<0.0001). In the histopathological evaluation, the angle of severe medial smooth muscle cell loss was largest for Ranger followed by IN.PACT and Lutonix (12.8 [8.0-20.4] degree vs 1.4 [1.2-5.2] degree vs 0.8 [0.5-2.5] degree, respectively), with significant differences for Ranger vs IN.PACT (p=0.007) and Ranger vs Lutonix (p=0.002). However, paclitaxel concentrations of distal skeletal muscles were lowest for Lutonix, followed by Ranger and IN.PACT (12 [1-58] pmol/mg vs 15 [13-21] pmol/mg vs 42 [19-108] pmol/mg, respectively, p<0.0001). The numbers of arteries with downstream DCB effects were highest for IN.PACT, followed by Ranger and Lutonix (Ranger vs IN.PACT vs Lutonix, 3 [3-4] vs 4 [3-7] vs 2 [1-2], respectively), which was consistent with the measured tissue paclitaxel concentrations. CONCLUSION: These findings suggest that Ranger demonstrates the strongest paclitaxel effect, as well as the second-best effect regarding distal particulate embolization, making it a good treatment option for patients with peripheral artery disease among the 3 DCBs evaluated in the current study. Further clinical head-to-head comparisons with larger numbers of patients are needed to explore which DCB is the most effective and safe treatment option.Clinical Impact:The findings of the current preclinical study suggests that Ranger demonstrates the strongest paclitaxel effect, as well as the second-best effect regarding distal particulate embolization making it a good treatment for patients with intermittent claudication and chronic limb-threatening ischemia.

Poor Below Knee Runoff Impacts Femoropopliteal Stent Failure and Fluoropolymer Antithrombotic Effect in Healthy Swine Model.

OBJECTIVE: Poor below knee (BTK) runoff is a predictor of stent failure after endovascular femoropopliteal artery treatment; however, lack of pathological evaluation has prevented characterisation of stent failure. The study aimed to investigate the impact of poor BTK runoff and the antithrombotic effect of the polymer of fluoropolymer coated paclitaxel eluting stents (FP-PESs) in a healthy swine femoropopliteal artery model. METHODS: FP-PESs and bare metal stents (BMSs) and FP-PES and polymer free paclitaxel coated stents (PF-PCSs) were implanted in the bilateral femoral arteries of healthy swine (n = 6, respectively) following coil embolisation in both tibial arteries to induce poor BTK runoff. Histological assessment and intravascular imaging device evaluation were performed at one month. The Japanese Association for Laboratory Animal Science approved the study protocol (reference number: IVT22-90). RESULTS: Optical coherence tomography showed significantly lower percent area stenosis in FP-PES compared with BMS (37.3%, [interquartile range (IQR), 25.6 - 54.3] % vs. 92.5% [IQR, 75.5 - 96.1] %, respectively, p = .031), and PF-PCS (8.3% [IQR, 4.5 - 27.0] % vs. 31.2% [IQR, 23.3 - 52.2] %, respectively, p = .031). Histopathological evaluation demonstrated that thin fibrin attachment without re-stenosis was the most dominant neointimal tissue characteristic in FP-PES. On the other hand, neointimal tissue characteristics with significant restenosis of BMS and PF-PCS were mainly organising or organised thrombus. CONCLUSION: Organising and or organised thrombus attachment due to poor BTK runoff was the main cause of in stent restenosis of the swine femoral artery. FP-PES demonstrated the least percent area stenosis, suggesting the importance of the antithrombotic effect of polymer.

Single-Nucleotide Polymorphisms, c.415C > T (Arg139Cys) and c.416G > A (Arg139His), in the NUDT15 Gene Are Associated with Thiopurine-Induced Leukopenia.

While nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene polymorphism Arg139Cys (rs116855232) is known to be a risk factor for thiopurine-induced severe leukopenia, association with the NUDT15 gene polymorphism Arg139His (rs147390019) has not yet been clarified. In addition, the accuracy of TaqMan PCR to assess these two polymorphisms has not been investigated. In this study, we evaluated TaqMan PCR for detection of the NUDT15 single-nucleotide polymorphisms (SNPs) and examined the clinical impact of Arg139His on thiopurine-induced leukopenia. First, we demonstrated that a TaqMan PCR assay successfully detected the Arg139His polymorphism of NUDT15 in clinical samples. Next, the NUDT15 gene polymorphisms (Arg139Cys and Arg139His) were separately analyzed by TaqMan Real-Time PCR in 189 patients from August 2018 to July 2019. The incidences of leukopenia within 2 years were 16.2, 57.9, and 100% for arginine (Arg)/Arg, Arg/cysteine (Cys), and Arg/histidine (His), respectively. The leukopenia was significantly increased in Arg/Cys and Arg/His compared with Arg/Arg. This retrospective clinical study indicated that, in addition to Arg139Cys, Arg139His may be clinically associated with a high risk of leukopenia. Pharmacogenomics will help in selecting drugs and determining the individualized dosage of thiopurine drugs.

Dose Individualization of Oral Multi-Kinase Inhibitors for the Implementation of Therapeutic Drug Monitoring.

Oral multi-kinase inhibitors have transformed the treatment landscape for various cancer types and provided significant improvements in clinical outcomes. These agents are mainly approved at fixed doses, but the large inter-individual variability in pharmacokinetics and pharmacodynamics (efficacy and safety) has been an unsolved clinical issue. For example, certain patients treated with oral multi-kinase inhibitors at standard doses have severe adverse effects and require dose reduction and discontinuation, yet other patients have a suboptimal response to these drugs. Consequently, optimizing the dosing of oral multi-kinase inhibitors is important to prevent over-dosing or under-dosing. To date, multiple studies on the exposure-efficacy/toxicity relationship of molecular targeted therapy have been attempted for the implementation of therapeutic drug monitoring (TDM) strategies. In this milieu, we recently conducted research on several multi-kinase inhibitors, such as sunitinib, pazopanib, sorafenib, and lenvatinib, with the aim to optimize their treatment efficacy using a pharmacokinetic/pharmacodynamic approach. Among them, sunitinib use is an example of successful TDM implementation. Sunitinib demonstrated a significant correlation between drug exposure and treatment efficacy or toxicities. As a result, TDM services for sunitinib has been covered by the National Health Insurance program in Japan since April 2018. Additionally, other multi-kinase targeted anticancer drugs have promising data regarding the exposure-efficacy/toxicity relationship, suggesting the possibility of personalization of drug dosage. In this review, we provide a comprehensive summary of the clinical evidence for dose individualization of multi-kinase inhibitors and discuss the utility of TDM of multi-kinase inhibitors, especially sunitinib, pazopanib, sorafenib, and lenvatinib.

Thyroid Dysfunction Related to the Antiangiogenic VEGFR2-Binding Monoclonal Antibody Ramucirumab: A Series of 14 Cases and a Descriptive Study.

Hypothyroidism is a well-established toxicity of small-molecule anti-vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors. However, its association with anti-VEGF biologics is uncertain. The aim of this study was to investigate the incidence, time course, clinical features, and severity of thyroid dysfunction in patients receiving ramucirumab (an antiangiogenic VEGF receptor 2-binding monoclonal antibody). After retrospectively reviewing electronic medical records from September 2015 to December 2018 at Kyoto-Katsura Hospital, we identified 38 patients who received ramucirumab and had thyroid function testing available to review (case series). We also evaluated the change of thyroid-stimulating hormone (TSH) level during ramucirumab chemotherapy in 16 out of 38 patients who were regularly confirmed TSH (descriptive study). A total of 14 (36.8%) patients developed thyroid dysfunction (TSH >10 mU/L) after ramucirumab chemotherapy. Thyroid autoantibodies were detected in one of the 10 patients (10.0%) who were tested for thyroid autoantibodies. The median time to onset of thyroid dysfunction after ramucirumab initiation was 275 (range, 63-553) days. Levothyroxine replacement was needed in 10 (71.4%) patients. Sixteen patients had thyroid function regularly monitored; the mean TSH level was significantly increased after ramucirumab chemotherapy compared with that at baseline (10.7 ± 10.0 mU/L vs. 4.1 ± 2.8 mU/L; p < 0.01). Our findings indicate that ramucirumab can result in thyroid dysfunction. We propose that thyroid function testing should be performed regularly to detect hypothyroidism and guide its management in patients receiving ramucirumab chemotherapy.

Oral mucositis associated with anti-EGFR therapy in colorectal cancer: single institutional retrospective cohort study.

BACKGROUND: Chemotherapy-induced oral mucositis impairs the quality of life. The difference in severity of oral mucositis between different anti-epidermal growth factor receptor (EGFR) antibodies combined with cytotoxic drugs in colorectal cancer is unclear. The aim of this study was to investigate the differences in oral mucositis between panitumumab (Pmab) and cetuximab (Cmab) combined with 5-fluorouracil (5-FU). METHODS: We conducted a retrospective cohort study. A total of 75 colorectal cancer outpatients treated with an anti-EGFR antibody combined with FOLFOX, FOLFIRI, or 5-FU/leucovorin as the first- to third-line treatment were included. The primary endpoint was the incidence of grade 2-3 oral mucositis. The secondary endpoint was the time to onset of oral mucositis. We also compared the incidence of toxicities of interest, skin toxicity, hypomagnesaemia and neutropenia, and time to treatment failure (TTF) between the two groups. RESULTS: Thirty-two patients treated with Pmab and 43 patients treated with Cmab were evaluated. Patient characteristics were similar between the two groups. The incidence of grade 2-3 oral mucositis was significantly higher with Pmab than with Cmab (31.3% vs 9.3%, P < 0.05). Moreover, the incidence of grade 3 oral mucositis was significantly higher in patients treated with Pmab (18.8% vs 0%, P < 0.01). The mean (SD) cycles to onset of the worst oral mucositis was 3.0 (2.9) in the Pmab group and 2.3 (1.7) in the Cmab group (P = 0.29). Oral mucositis was characterized by glossitis and cheilitis. The incidences of other toxicities were the following (Pmab vs Cmab): grade 2-3 skin toxicity: 68.8% vs 74.4% (P = 0.61), grade 2-3 hypomagnesaemia: 9.3% vs 7.0% (P = 1.00), grade 3-4 neutropenia: 28.1% vs 37.2% (P = 0.46). The median TTF was not significantly different, i.e., 223 days vs 200 days (P = 0.39) for Pmab vs Cmab. CONCLUSIONS: Pmab-based chemotherapy resulted in significantly higher grades of oral mucositis compared with Cmab-based chemotherapy. The oral condition should be monitored carefully and early supportive care should be provided for patients treated with Pmab-based chemotherapy.

Quantification of Sorafenib in Human Serum by Competitive Enzyme-Linked Immunosorbent Assay.

The multikinase inhibitor sorafenib has been used in the treatment of hepatocellular carcinoma, renal cell carcinoma, and differentiated thyroid carcinoma. Here we have demonstrated the production of the first specific antibody against sorafenib. Anti-sorafenib serum was obtained by immunizing mice with an antigen conjugated with bovine serum albumin and carboxylic modified 4-(4-aminophenoxy)-N-methyl-2-pyridinecarboxamide (AMPC) using the N-succinimidyl ester method. Enzyme labeling of sorafenib with horseradish peroxidase was similarly performed using carboxylic modified AMPC. A simple competitive enzyme-linked immunosorbent assay (ELISA) for sorafenib was developed using the principle of direct competition between sorafenib and the enzyme marker for anti-sorafenib antibody, which had been adsorbed by the plastic surface of a microtiter plate. Serum sorafenib concentrations lower than 0.04 µg/mL were reproducibly measurable using the ELISA. This ELISA was specific to sorafenib and showed very slight cross-reactivity (2.5%) with a major metabolite, sorafenib N-oxide. The values of serum sorafenib levels from 32 patients measured by this ELISA were comparable with those measured by HPLC, and there was a strong correlation between the values determined by the two methods (Y=1.016X-0.137, r=0.979). The specificity and sensitivity of the ELISA for sorafenib should provide a valuable new tool for use in therapeutic drug monitoring and pharmacokinetic studies of sorafenib.

Population Pharmacokinetics and Therapeutic Efficacy of Febuxostat in Patients with Severe Renal Impairment.

The aim of the present study was to determine the influence of severe renal dysfunction (estimated glomerular filtration rate <30 ml/min/1.73 m(2), including hemodialysis) on the pharmacokinetics and therapeutic effects of febuxostat using a population pharmacokinetic analysis. This study recruited patients with hyperuricemia who were initially treated with allopurinol, but were switched to febuxostat, and it consists of 2 sub-studies: a pharmacokinetic study (26 patients) and retrospective efficacy evaluation study (51 patients). The demographic and clinical data of patients were collected from electronic medical records. Plasma febuxostat concentrations were obtained at each hospital visit. Population pharmacokinetic modeling was performed with NONMEM version 7.2. A total of 128 plasma febuxostat concentrations from 26 patients were used in the population pharmacokinetic analysis. The data were best described by a 1-compartment model with first order absorption. Covariate analysis revealed that renal function did not influence the pharmacokinetics of febuxostat, whereas actual body weight significantly influenced apparent clearance and apparent volume of distribution. The retrospective efficacy analysis showed the favorable therapeutic response of febuxostat switched from allopurinol in patients with moderate to severe renal impairment. No serious adverse event associated with febuxostat was observed irrespective of renal function. The population pharmacokinetic analysis and therapeutic analysis of febuxostat revealed that severe renal dysfunction had no influence on the pharmacokinetic parameters of febuxostat. These results suggest that febuxostat is tolerated well by patients with severe renal impairment.

Reduction in gastrointestinal toxicity by gastric secretion inhibitors during S-1 monotherapy for patients with gastric cancer.

The purpose of this study was to retrospectively examine the effect of concomitant administration of gastric secretion inhibitors or gastrectomy on the frequency of gastrointestinal toxicity caused by 5-fluorouracil (5-FU) in gastric cancer patients receiving chemotherapy with S-1. In 62 gastric cancer patients treated with S-1 alone, data relating to the occurrence of gastrointestinal toxicity (diarrhea, vomiting, and nausea) and possible contributing factors were retrospectively collected, and logistic regression analysis was performed. Time-to-event data relating to the occurrence of gastrointestinal toxicity were also collected, and the effect of gastric secretion inhibitors on the time-to-event profiles was examined using a log-rank test. Logistic regression analysis suggested that the frequency of gastrointestinal toxicity was significantly reduced by the administration of gastric secretion inhibitors (p=0.01; odds ratio, 0.197; 95% confidence interval (CI), 0.056-0.694) and that gastrointestinal toxicity correlated with the estimated glomerular filtration rate (p=0.04; odds ratio, 0.956; 95% CI, 0.916-0.997). The median time-to-event of gastrointestinal toxicity was 85 d for patients that received gastric secretion inhibitors, which was significantly different from the 42 d for patients that did not receive the inhibitors (p=0.02, log-rank test). No clear effect of gastrectomy was found in the present study. The prophylactic use of gastric secretion inhibitors in gastric cancer patients treated with S-1 may decrease and delay the occurrence of gastrointestinal toxicity.

Relationships of Proton Pump Inhibitor-Induced Renal Injury with CYP2C19 Polymorphism: A Retrospective Cohort Study.

Proton pump inhibitors (PPIs) have recently been reported to be linked with nephrotoxicity. PPIs are metabolized mainly or partly by cytochrome P450 2C19 (CYP2C19). However, the relationship between CYP2C19 genetic polymorphism and PPI-induced nephrotoxicity is unclear. In this study, we aimed to analyze the association between the time of occurrence of renal injury by PPIs, including lansoprazole, esomeprazole, rabeprazole, and vonoprazan, and CYP2C19 metabolizer status classified by CYP2C19 genotypes. Patients prescribed PPIs were reviewed in this retrospective cohort study. The primary outcome was the time to a 30% decrease in estimated glomerular filtration rate (eGFR) from baseline. In patients treated with lansoprazole, the time to a 30% decrease in eGFR for the CYP2C19 poor metabolizer (PM) group was significantly shorter than that for the non-PM group (hazard ratio for PM vs. non-PM, 2.43, 95% confidence interval, 1.21 to 4.87, P = 0.012). In contrast, in patients that received esomeprazole, rabeprazole, or vonoprazan, no significant differences were found in the time to a 30% decrease in eGFR between non-PM and PM groups. The adjusted hazard ratios for the time to a 30% eGFR decrease in patients treated with lansoprazole were significantly higher for CYP2C19 PM, hypertension, and a history of myocardial infarction. In conclusion, this retrospective study showed that CYP2C19 metabolizer status was associated with the time to a 30% eGFR decrease in patients treated with lansoprazole, but not with esomeprazole, rabeprazole, or vonoprazan.

Vericiguat and transcatheter edge-to-edge mitral valve repair for combined post- and pre-capillary pulmonary hypertension due to left ventricular low ejection fraction and functional mitral regurgitation.

A 66-year-old female was diagnosed with combined post- and pre-capillary pulmonary hypertension due to heart failure with reduced ejection fraction (47 %) and functional mitral regurgitation [mean pulmonary arterial wedge pressure: 27 mmHg; pulmonary arterial pressure: 91/30 (56) mmHg; pulmonary vascular resistance: 12.9 Wood units; and cardiac index: 1.77 L/min/m2]. Following treatment with vericiguat (a novel oral soluble guanylate cyclase stimulator), hemodynamics improved [mean pulmonary arterial wedge pressure: 27 mmHg; pulmonary arterial pressure: 54/26 (35) mmHg; pulmonary vascular resistance: 2.2 Wood units; and cardiac index: 2.80 L/min/m2]. Therefore, transcatheter edge-to-edge repair for functional mitral regurgitation was performed. One month later, further improvement in hemodynamics was confirmed. Learning objective: Vericiguat (a novel oral soluble guanylate cyclase stimulator) and transcatheter edge-to-edge mitral valve repair may improve combined post- and pre-capillary pulmonary hypertension due to low ejection fraction of the left ventricle and functional mitral regurgitation.

Pre-existing autoimmune disease as a risk factor for immune-related adverse events in cancer patients receiving immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have been widely used as standard therapies for various cancers. However, in 20-30% of cases, ICIs can lead to immune-related adverse events (irAEs), which sometimes require discontinuation of treatment. Due to the increased risk of irAEs, patients with pre-existing autoimmune diseases (AI) are often advised against receiving ICIs. However, there has not been sufficient objective risk assessment for AI. In our study, we conducted logistic regression analysis to assess the risk of irAEs by analyzing 478 cases that received anti-PD-(L)1 Ab and/or anti-CTLA4 Ab at our hospital between April 3, 2017, and May 24, 2022. Among these cases, 28 (5.9%) had pre-existing AI. We selected several independent factors for analysis: gender, age, performance status (PS), cancer type, type of ICI, type of combined anti-cancer agents, best overall response, and pre-existing AI. The adjusted odds ratio (OR) of AI for irAE occurrence was 2.52 [95% CI: 1.08-5.86] (p = 0.033), and the adjusted OR of AI for ICI discontinuation due to irAE was 3.32 [1.41-7.78] (p = 0.006). Patients with pre-existing AI experienced a significantly shorter irAE-free survival time compared to those without AI (median irAE-free survival: 5.7 months [95% CI: 3.5-7.8] vs 10.4 months [95% CI: 7.9-12.9], respectively, p = 0.035). Frequently observed irAEs in full ICI cohort, such as dermatologic issues (7.5%), pneumonitis (7.1%), hepatitis (4.6%), and hypothyroidism (4.2%), were often accompanied by pre-existing AI. Furthermore, pre-existing AI flared up in 6 cases (37.5% in AI-positive irAE-positive cases). The activity of AI was not related to the occurrence of irAEs. Grade 3 or higher irAEs were observed in 6 out of 20 (30.0%) cases in AI-accompanied patients complicated with irAEs. Although having a complicated AI increases the risk of irAEs, it may not necessarily be a contraindication for ICI treatment if closely monitored. (292<300 characters).

Histological evaluation of vascular changes after excimer laser angioplasty for neointimal formation after bare-metal stent implantation in rabbit iliac arteries.

BACKGROUND: Excimer laser is used to treat coronary artery disease, especially in case of lesions with thrombus and in-stent restenosis (ISR). However, there are no in vivo preclinical studies that have evaluated the pathological reactions of the vessel wall after excimer laser ablation. METHODS: Bare-metal stents were placed in the external iliac arteries of six healthy rabbits. Twenty-eight days later, excimer laser ablation was performed with low-power (45 (fluency)/25 (rate)) in one side, and high-power (60/40) in the opposite side, followed by optical coherence tomography (OCT) evaluation. Rabbits were sacrificed 15 min after the procedure, and histological assessment was performed. RESULTS: Morphometry analysis of OCT showed similar stent and lumen size between low-power and high-power group. Histological evaluation suggested endothelial cell loss, fibrin deposition, and tissue loss. The low-power group showed significantly less pathological changes compared with the high-power group: angle of endothelial cell loss, 32.4° vs. 191.7° (interquartile range, 8.8°-131.7° vs. 125.7°-279.5°; p < 0.01); fibrin deposition, 1.1° vs. 59.6° (0.0°-70.4° vs. 31.4°-178.4°; p = 0.03); and tissue loss 0.0° vs. 18.2° (0.0°-8.7° vs. 0.0°-42.7°; p = 0.03). CONCLUSIONS: The pathological changes in neointima were more prominent after high-power excimer laser ablation than after low-power excimer laser. To improve safety in clinical practice, understanding the pathological changes of tissues after excimer laser in lesions with ISR is essential.

Feasibility and Outcome of Transjugular Intracardiac Echocardiography-Guided Transcatheter Aortic Valve Replacement.

Background: There are limited data on the impact of intracardiac echocardiography (ICE)-guided transcatheter aortic valve replacement (TAVR) on the new permanent pacemaker implantation (PPMI) rate. Objectives: This study investigated the feasibility and outcome of transjugular ICE (TJ-ICE) -guided TAVR, by visualizing the relationship between the membranous septum (MS) and the transcatheter aortic valve (TAV). Methods: Among patients with severe aortic stenosis who underwent TAVR between February 2017 and June 2020, this study enrolled a total of 163 patients with TJ-ICE-guided TAVR. MS length was measured by ICE. The primary endpoint of this study was the incidence of new PPMI at 30 days. Results: The mean age of the patients in this study was 84.9 ± 4.6 years, and 71.2% of the patients were female. Device success was 96.3% with TJ-ICE guidance. A TJ-ICE-related complication occurred in 1 case (0.6%). The median length of the MS was 5.8 mm (IQR: 5.0-6.9 mm). Excellent intraobserver (intraclass correlation coefficient [ICC]: 0.94; 95% CI:0.79-0.98; P < 0.001) and interobserver (ICC: 0.93; 95% CI: -0.05 to 0.98; P < 0.001) agreements were shown. The new PPMI rate was 6.7% at 30 days without a significant difference between balloon-expandable valves and self-expandable valves (3.4% vs 8.7%; P = 0.226). Patients with a TAV implantation depth less than MS length had a significantly lower incidence of new PPMI compared with patients with a TAV implantation depth greater than MS length (2.1% vs 13.4%; P = 0.005), regardless of baseline right bundle branch block presence (6.7% vs 66.7%; P = 0.004) or absence (1.2% vs 8.2%; P = 0.041). Conclusions: TJ-ICE-guided TAVR demonstrated remarkable feasibility and safety. The TJ-ICE-guided final TAV position had a significant impact on the new PPMI rate. (Tokai Valve Registry; UMIN000036671).

Analysis of Risk Factors for High-dose Cisplatin-induced Renal Impairment in Head and Neck Cancer Patients.

BACKGROUND/AIM: Concurrent chemoradiotherapy with high-dose cisplatin (CDDP-RT) is the standard therapy for advanced head and neck cancer; however, due to CDDP-induced renal impairment, dose reduction or discontinuation is frequently required. Therefore, the identification of risk factors for renal impairment is of importance to improve the efficacy and safety of CDDP-RT. PATIENTS AND METHODS: We retrospectively investigated risk factors for renal impairment in advanced head and neck cancer patients receiving CDDP-RT. Renal impairment was defined as a >25% decrease from baseline in estimated glomerular filtration rate within 14 days after CDDP administration in the first cycle. RESULTS: Of the 82 patients analyzed in this study, 21 (26%) patients developed renal impairment. Multivariate logistic regression analysis showed that concomitant use of a calcium channel blocker or lower hemoglobin levels significantly contributed to the increased risk of CDDP-induced renal impairment (odds ratio=3.60, 95% confidence interval=1.04-12.40; odds ratio=0.71, 95% confidence interval=0.50-0.99, respectively), while concomitant use of proton pump inhibitors was a factor associated with a decreased risk of CDDP-induced renal impairment (odds ratio=0.20, 95% confidence interval=0.04-0.86). CONCLUSION: Renal function of patients receiving calcium channel blocker or patients with lower hemoglobin levels should be monitored cautiously when receiving CDDP-RT.

Sex Differences in Clinical Outcomes Among Patients With COVID-19 and Cardiovascular Disease　- Insights From the CLAVIS-COVID Registry.

Background: Male sex is associated with a worse clinical course and outcomes of COVID-19, particularly in older patients. However, studies on COVID-19 patients with cardiovascular disease and/or risk factors (CVDRF), which are representative risk factors of COVID-19, are limited. In this study, we investigated the effect of sex on the outcomes of hospitalized COVID-19 patients with CVDRF. Methods and Results: We analyzed 693 COVID-19 patients with CVDRF. Patients were divided into 2 groups based on sex, and baseline characteristics and in-hospital outcomes were compared between the 2 groups. The mean age of the 693 patients was 68 years; 64.8% were men and 96.1% were Japanese. In a univariate analysis model, sex was not significantly associated with in-hospital mortality (odds ratio [OR] 1.22; 95% confidence interval [CI] 0.74-2.02; P=0.43). However, men had higher in-hospital mortality than women, especially among older (age ≥80 years) patients (OR 2.21; 95% CI 1.11-4.41; P=0.024). After adjusting for age and pivotal risk factors (hypertension, diabetes, heart failure, coronary artery disease, chronic lung disease, and chronic kidney disease), multivariate analysis suggested that male sex was an independent predictor of in-hospital mortality (OR 2.20; 95% CI 1.23-3.92; P=0.008). Conclusions: In this post hoc analysis of a nationwide registry focusing on patients with COVID-19 and CVDRF, men had higher in-hospital mortality than women, especially among older patients.

Severe Skin Disorders Due to Sorafenib Use After Nivolumab Treatment in Renal Cell Carcinoma Patients.

BACKGROUND: We report two cases in which severe skin disorders developed during sorafenib treatment in patients with renal cell carcinoma (RCC) who had previously received nivolumab. CASE REPORT: Case 1: A 50-year-old man with RCC received nivolumab as the fifth-line therapy followed by sorafenib as the sixth-line therapy. On day 15 of sorafenib administration, the patient was hospitalized with systemic erythema multiforme, acne-like skin rash, and hand-foot syndrome. Case 2: A 40-year-old man with RCC received nivolumab as the second-line therapy followed by sorafenib as the fifth-line treatment. On day 12 of sorafenib administration, the patient was hospitalized with an acne-like skin rash and hand-foot syndrome. The skin disorders in the two cases improved within 2-3 weeks after sorafenib discontinuation and the start of treatment with topical and oral steroids. CONCLUSION: When using sorafenib in patients previously treated with nivolumab, close attention should be paid to the onset of serious skin disorders.

Exploratory analysis of target concentration of lenvatinib in the treatment of hepatocellular carcinoma.

PURPOSE: We aimed to evaluate exposure-toxicity/efficacy relationship of lenvatinib by determining its target trough concentration for patients with hepatocellular carcinoma (HCC). METHODS: In this retrospective, observational study, 28 HCC patients who had been treated with lenvatinib were enrolled between August 2018 and April 2020. We evaluated the association between the trough lenvatinib concentration and occurrence of grade ≥ 3 toxicities. Additionally, we estimated the association of the trough lenvatinib concentration with responder status (disease control; complete response, partial response, or stable disease), and progression-free survival (PFS). RESULTS: The mean trough lenvatinib concentration was significantly higher in the group with grade ≥ 3 toxicity (n = 15) than in the group with grade ≤ 2 toxicity (n = 13). Based on the receiver operating characteristic curve, the threshold values of the trough lenvatinib concentrations for predicting grade ≥ 3 toxicities and responder status were 71.4 ng/mL [area under the curve (AUC) 0.86, 95% confidence interval (CI) 0.71-1.00; p < 0.05] and 36.8 ng/mL (AUC 0.95, 95% CI 0.85-1.00; p < 0.05), respectively. Lenvatinib concentrations of 36.8-71.4 ng/mL resulted in longer PFS than concentrations < 36.8 ng/mL and ≥ 71.4 ng /mL [median 13.3 months (36.8-71.4 ng/mL) vs. 3.5 months (< 36.8 ng/mL) and 7.8 months (≥ 71.4 ng /mL), respectively]. CONCLUSIONS: Considering these results, we propose that the target trough concentration of lenvatinib could be 36.8-71.4 ng/mL for maintaining disease control status and reducing grade ≥ 3 toxicity in the treatment of HCC.

Sorafenib exposure and its correlation with response and safety in advanced hepatocellular carcinoma: results from an observational retrospective study.

PURPOSE: Severe adverse events frequently occur in patients treated with sorafenib, whereas some patients have suboptimal response to sorafenib. We aimed to evaluate the association of sorafenib-induced toxicities and clinical outcomes with the pharmacokinetics of sorafenib in patients with hepatocellular carcinoma (HCC). METHODS: This was a retrospective, observational study in which 26 HCC patients who had been treated with sorafenib were enrolled between September 2010 and March 2015. The association between trough sorafenib concentration and occurrence of grade ≥ 3 toxicities was evaluated. In addition, we estimated the association of trough sorafenib concentration with overall survival (OS). RESULTS: The median sorafenib concentration was 2.91 µg/mL (range 0.74-8.8 µg/mL). Based on the receiver operating characteristic curve, the threshold value of the trough sorafenib concentration for predicting grade ≥ 3 toxicities and responder (complete response or partial response at best response, or stable disease for ≥ 3 months) was 3.45 µg/mL [area under the curve (AUC) 0.74, 95% confidence interval (CI) 0.54-0.93; p <0.05] and 1.40 µg/mL (AUC 0.97, 95% CI 0.97-1.00; p <0.05), respectively. OS of patients with sorafenib 1.40-3.45 µg/mL had a tendency to be longer than those of patients administered < 1.40 µg/mL and ≥ 3.45 µg/mL [median 17.8 months (1.40-3.45 µg/mL) vs. 5.3 months (< 1.40 µg/mL) and 9.5 months (≥ 3.45 µg/mL)]. CONCLUSIONS: From results of this study, we proposed that the target range of sorafenib may be a trough concentration of 1.40-3.45 µg/mL in patients with HCC.