Lipid profile and risk factors for neoatherosclerosis after drug-eluting stent implantation in acute coronary syndrome.

BACKGROUND: Predictors of neoatherosclerosis in patients who received primary percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) remain unclear. OBJECTIVE: The aim of this study is to investigate the frequency and risk factors of neoatherosclerosis 1-year after the onset of ACS. METHODS: This study investigated 83 patients who underwent PCI for ACS followed by 1-year follow-up optical coherence tomography. The patients were categorized into the neoatherosclerosis (n = 11) and non-neoatherosclerosis groups (n = 72). Baseline characteristics, PCI procedures, medical therapies, and blood tests at 1-year, including detailed lipid profiles, were compared between the two groups. RESULTS: Diabetes mellitus was more prominent in the neoatherosclerosis than in the non-neoatherosclerosis group (45% vs. 17 %, respectively, p = 0.03). Total cholesterol (171 ± 37 mg/dL vs. 145 ± 25 mg/dL, respectively, p < 0.01), non-high-density lipoprotein cholesterol (HDL-C) (124 ± 36 mg/dL vs. 94 ± 24 mg/dL, respectively, p < 0.01), low-density lipoprotein cholesterol (94 ± 36 mg/dL vs. 72 ± 19 mg/dL, respectively, p < 0.01), and lipoprotein (a) (Lp[a]) (70 [19-112] mg/dL vs. 10 [3-25] mg/dL, respectively, p = 0.03) at follow-up were significantly higher in the neoatherosclerosis group. Multivariate analysis revealed that neoatherosclerosis was associated with high serum non-HDL-C (odds ratio [OR]: 1.075; 95 % confidence interval [CI]: 1.011-1.144; p < 0.01) and high serum Lp(a) levels (>30 mg/dL) (OR: 11.0; 95 % CI: 1.492-81.02; p = 0.02). CONCLUSION: Poorly controlled non-HDL-C and Lp(a) would be risk factors of neoatherosclerosis in patients 1-year after ACS.

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).

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

Granisetron plus aprepitant versus granisetron in preventing nausea and vomiting during CHOP or R-CHOP regimen in malignant lymphoma: a retrospective study.

BACKGROUND: Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) regimen includes a high dose of prednisolone (100 mg/body), which exhibits an anticancer and antiemetic effect. However, its optimal use for antiemetic therapy has not been established yet. We assessed the efficacy of granisetron plus aprepitant versus granisetron for CHOP or rituximab-CHOP (R-CHOP) regimen-induced nausea and vomiting in malignant lymphoma. METHODS: This retrospective and observational clinical study included patients who received CHOP or R-CHOP regimen as initiating chemotherapy between July 2010 and March 2016 (N = 39). Patients were assigned to an aprepitant [aprepitant (125 mg on day 1, 80 mg on days 2-3) plus granisetron (3 mg); n = 15] or control regimen group [granisetron (3 mg); n = 24]. Complete response (CR), defined as no vomiting and no use of rescue therapy during overall phase (0-120 h), was the primary endpoint. Secondary endpoints included the time to first vomiting and using rescue medication and complete protection (CP) defined as no vomiting and no retching and/or no nausea and no rescue therapy. The patient records were investigated, and data were retrospectively analyzed. RESULTS: CR rate CP rates did not significantly differ between the groups during the observation period (80.0% versus 83.3%, p = 1.000; and 80.0% versus 79.2%, p = 1.000, respectively). Additionally, the time to first vomiting and using rescue medication in did not significantly differ between the groups (p = 0.909). CONCLUSIONS: This study suggests that granisetron alone could be one treatment option in the management of CINV in patients with non-Hodgkin lymphoma receiving CHOP or R-CHOP regimen.

Impact of prior bortezomib therapy on the incidence of lenalidomide-induced skin rash in multiple myeloma: a propensity score-matched multi-institutional cohort study.

This retrospective cohort study was conducted to investigate the association between prior bortezomib (BOR) therapy and lenalidomide (LEN)-induced rash in multiple myeloma (MM) patients. Eligible MM patients initially treated with LEN were divided into two propensity score-matched cohorts according to the presence or absence of prior BOR therapy. The primary endpoint of the study was rash incidence. We evaluated 144 patients and each cohort contained 43 patients after matching propensity-score. Rash incidence significantly decreased in patients with prior BOR therapy than in those without (30% vs. 53%, p < .05). Moreover, patients with rash showed a significantly higher incidence of eosinophilia within 1 month after LEN initiation than those without rash. Our findings indicate that prior BOR therapy may reduce the incidence of LEN-induced rash, which may be characterized by eosinophilia. Accordingly, in patients who discontinued LEN therapy due to rash, LEN re-treatment may be successful after BOR therapy.

Exploratory Investigation of Target Pazopanib Concentration Range for Patients With Renal Cell Carcinoma.

BACKGROUND: Severe adverse events frequently occur in patients treated with pazopanib, necessitating dose reduction and discontinuation. However, information on the exposure-toxicity relationship is limited. PATIENTS AND METHODS: For this retrospective and observational clinical study, we examined 27 patients with renal cell carcinoma treated with pazopanib and enrolled between October 2014 and March 2018. The primary goal was to evaluate the association between trough pazopanib concentration and occurrence of grade ≥ 3 toxicities, and secondarily, to estimate the association between trough pazopanib concentration and objective response rate. RESULTS: Mean trough pazopanib concentration was significantly higher in the grade ≥ 3 toxicity group (n = 9) than in the grade ≤ 2 toxicity group (n = 18). Based on the receiver operating characteristic curve, the threshold value of trough pazopanib concentration for predicting grade ≥ 3 toxicities was 50.3 µg/mL (area under the curve, 0.85; 95% confidence interval, 0.70-0.99; P < .05). In the pazopanib < 20.5 µg/mL group (n = 3), no patient experienced an objective response. Objective response rates between patients with 20.5 to 50.3 µg/mL pazopanib (n = 11) and patients with ≥ 50.3 µg/mL (n = 13) were similar (45.5% vs. 46.2%). CONCLUSION: From results of this study, the target trough pazopanib concentration range may be 20.5 to 50.3 µg/mL for patients with renal cell carcinoma.