Impact of prior bevacizumab therapy on the incidence of ramucirumab-induced proteinuria in colorectal cancer: a multi-institutional cohort study.

BACKGROUND: The association between prior bevacizumab (BEV) therapy and ramucirumab (RAM)-induced proteinuria is not known. We aimed to investigate this association in patients with metastatic colorectal cancer (mCRC). METHODS: mCRC patients who received folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus RAM were divided into with and without prior BEV treatment groups. The cumulative incidence of grade 2-3 proteinuria and rate of RAM discontinuation within 6 months (6M) after RAM initiation were compared between the two groups. RESULTS: We evaluated 245 patients. In the Fine-Gray subdistribution hazard model including prior BEV, age, sex, comorbidities, eGFR, proteinuria ≥ 2 + at baseline, and later line of RAM, prior BEV treatment contributed to proteinuria onset (P < 0.01). A shorter interval between final BEV and initial RAM increased the proteinuria risk; the adjusted odds ratios (95% confidence intervals) for the intervals of < 28 days, 28-55 days, and > 55 days (referring to prior BEV absence) were 2.60 (1.23-5.51), 1.51 (1.01-2.27), and 1.04 (0.76-1.44), respectively. The rate of RAM discontinuation for ≤ 6M due to anti-VEGF toxicities was significantly higher in the prior BEV treatment group compared with that in the no prior BEV treatment group (18% vs. 6%, P = 0.02). Second-line RAM discontinuation for ≤ 6M without progression resulted in shorter overall survival of 132 patients with prior BEV treatment (P < 0.01). CONCLUSION: Sequential FOLFIRI plus RAM after BEV failure, especially within 55 days, may exacerbate proteinuria. Its escalated anti-VEGF toxicity may negatively impact the overall survival.

[Association of D-dimer Levels with Complications after Subcutaneous Implantable Central Venous Port Placement in Combination Chemotherapy with Bevacizumab for Colorectal Cancer].

Bevacizumab(BV)combination chemotherapy in colorectal cancer under subcutaneously implanted central venous port (CVP)implantation may cause complications after the implantation. Measurement of D-dimer is recommended to predict thromboembolism and other complications, but its relevance to complications after CVP implantation remains unclear. In this study, we investigated the association between D-dimer and complications after CVP implantation in 93 patients with colorectal cancer who received BV combination chemotherapy. Complications after CVP implantation occurred in 26 patients (28%), and those with VTE showed higher D-dimer values at the onset of the complication. The D-dimer values of the patients with VTE displayed a sharp increase at the onset of the disease, while those with an abnormal CVP implantation site showed a more variable course. Measurement of D-dimer levels appeared useful in estimating the incidence of VTE and abnormal CVP implantation sites in post-CVP implantation complications of BV combination chemotherapy for colorectal cancer. Further, monitoring not only the quantitative values but also the fluctuations over time is also important.

Cardiovascular Toxicities Associated with Anaplastic Lymphoma Kinase Inhibitors: A Disproportionality Analysis of the WHO Pharmacovigilance Database (VigiBase).

INTRODUCTION: Recently, cases of cardiovascular toxicities, such as pericarditis, caused by anaplastic lymphoma kinase (ALK) inhibitors have been reported; however, whether these adverse events are common among all ALK inhibitors remains unclear. AIMS: This study aimed to clarify the cardiovascular toxicity profile of ALK inhibitors using an adverse event spontaneous report database. METHODS: We analyzed data from VigiBase, the WHO global database of individual safety reports, from its inception in 1968 to December 2021. We calculated the reporting odds ratio to evaluate the association between ALK inhibitors (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib) and 21 cardiovascular adverse events. Time to onset of pericarditis from ALK inhibitor administration was analyzed. RESULTS: Of the 27,994,584 reports, 19,911 involved treatment with ALK inhibitors. Among the 21 cardiovascular toxicities, only pericarditis signals were detected with all five ALK inhibitors (crizotinib [reporting odds ratios (ROR), 4.7; 95% CI 3.63-6.15], ceritinib [ROR, 12.9; 95% CI 9.37-17.79], alectinib [ROR, 4.8; 95% CI 3.15-7.42], brigatinib [ROR, 3.5; 95% CI 1.33-9.46], and lorlatinib [ROR, 6.4; 95% CI 3.60-11.22]). For torsade de pointes/QT prolongation, signals were detected with crizotinib (ROR, 5.0; 95% CI 3.72-6.77) and ceritinib (ROR, 4.2; 95% CI 2.17-8.05), whereas for hypertension, they were identified only with brigatinib (ROR, 3.9; 95% CI 2.88-5.20), and for heart failure, they were detected with alectinib (ROR, 2.2; 95% CI 1.60-2.90), crizotinib (ROR, 2.1; 95% CI 1.72-2.48), and lorlatinib (ROR, 2.0; 95% CI 1.27-3.23). Regarding time-to-onset analysis from drug administration to adverse event reporting, for pericarditis, it ranged from 52.5 days for alectinib to 166.5 days for crizotinib. CONCLUSIONS: Systematic evaluation of ALK inhibitor-associated adverse events revealed differences in the cardiotoxicity profiles among ALK inhibitors. Understanding the differences in the cardiovascular toxicity profile of each ALK inhibitor will contribute to safe drug therapy when switching between ALK inhibitors.

Characterization of Immune Checkpoint Inhibitor-Induced Myasthenia Gravis Using the US Food and Drug Administration Adverse Event Reporting System.

Myasthenia gravis (MG) is a rare but fatal adverse event of immune checkpoint inhibitors (ICIs). We assessed whether patient characteristics differed between those with ICI-related myasthenia gravis and those with idiopathic myasthenia gravis. Reports from the US Food and Drug Administration Adverse Event Reporting System were analyzed. Multivariate analyses were conducted to evaluate the associations between age, sex, and ICI treatment and the reporting rate of myasthenia gravis. Among 5 464 099 cases between 2011 and 2019, 53 447 were treated with ICIs. Myasthenia gravis was reported more often in ICI users. Multiple logistic regression analyses showed that the reporting rate of ICI-related myasthenia gravis did not differ significantly between men and women; however, it was higher in older people than in younger people (adjusted odds ratio, 2.4 [95%CI, 1.84-3.13]). We also investigated useful signs for the early detection of myositis and myocarditis, which are fatal when overlapping with ICI-related myasthenia gravis. Patients with elevated serum creatine kinase or troponin levels were more likely to have concurrent myositis and myocarditis. Unlike idiopathic myasthenia gravis, there was no sex difference in the development of ICI-related myasthenia gravis, which may be more common in older people. Considering the physiological muscle weakness that occurs in the elderly, it may be necessary to monitor ICI-related myasthenia gravis more closely in older people.

Fluoropyridmidine use and hypertriglyceridemia among Japanese patients: analysis of adverse event database.

Background The association between fluoropyrimidines except for capecitabine and the risk of hypertriglyceridemia is unclear. Objective To investigate hypertriglyceridemia in patients receiving fluoropyrimidines. Method This observational study used anonymized patient data recorded in the open-access Japanese Adverse Drug Event Report database. All fluoropyrimidine and taxane users were investigated. Results We identified 29,451 fluoropyrimidine users and 21,266 taxane users. Disproportionality for both hypertriglyceridemia and an increase in serum triglyceride levels was observed in fluoropyrimidine users compared with in taxane users (reporting odds ratio, 6.74; 95% confidence interval [CI] 2.05-22.17; P < .001). Multivariate logistic analysis showed that both hypertriglyceridemia and an increase in serum triglyceride levels among fluoropyrimidines users were significantly associated with doxifluridine use (odds ratio [OR] 42.50; 95% CI 5.34-338.00; P < .001), tegafur use (OR 9.56; 95% CI 2.08-43.90; P < .001), capecitabine use (OR 12.30; 95% CI 2.67-56.80; P < .001), and breast cancer (OR 5.61; 95% CI 1.07-29.50; P = .042). Conclusion This study suggests that the use of tegafur and doxifluridine is associated with an increased risk of hypertriglyceridemia similar to that with the use of capecitabine; in particular, fluoropyrimidine users with breast cancer may have a high risk of hypertriglyceridemia.

[Exploratory Study of the Risk Factors for Acute Kidney Injury in the Cisplatin Combination Chemotherapy for Solid Cancer].

In the present study, we investigated the rate of cisplatin(CDDP)-induced acute kidney injury(CIA)and examined its association with various clinical factors in the combination therapy with CDDP for solid cancers. A total of 726 cases of solid cancer that had been indicated for the CDDP combination regimen from December 2012 to December 2013 were enrolled. CIA occurred in 48 cases(6.6%). The multivariate analysis revealed that diabetes, the regular use of non-steroidal anti- inflammatory drugs(NSAIDs), first dose of CDDP, and severe hyponatremia(≥Grade 3)within one week after CDDP administration were significantly associated with an increased risk for CIA, whereas magnesium supplementation was associated with a significantly reduced risk for CIA. Particularly, diabetes and cardiovascular disease were identified as risk factors for CIA in patients with esophageal and head and neck cancers. Based on the results of this survey, it is important to formulate preventive measures, evaluate risk factors, and respond rapidly.

[Risk Factors of Thromboembolism in Colorectal Cancer Patients Receiving Combination Chemotherapy with Bevacizumab].

We investigated the incidence of thromboembolism in patients receiving combination chemotherapy with bevacizumab (BV)for colorectal cancer and examined its association with clinical factors. Between July 2007 and April 2014, 250 patients with colorectal cancer received combination chemotherapy with BV. Thromboembolism occurred in 24 cases(9.6%). Five predictive risk factors(platelet count B350,000/µL, hemoglobin <10 g/dL, leukocyte count>11,000/mL, body mass index B25.3 kg/m2, and D-dimer B1.44 µg/mL)were set based on a previous report, and the corresponding number of risk factors for thromboembolism and incidence of thromboembolism were examined. The results of multivariate analysis showed that the occurrence of 3 or more risk factors conferred a significant risk for the incidence of thromboembolism. Due to the increased risk of developing thromboembolism in such patients, special attention during management is required.

[Survey of Cholinergic Symptoms in Patients with Colorectal Cancer Who Were Receiving Irinotecan Hydrochloride Combination Chemotherapy].

We investigated the incidence of cholinergic symptoms related to irinotecan hydrochloride(CPT-11)and examined their association with clinical factors. The subjects were 61 patients with colorectal cancer for whom combination chemotherapy with CPT-11 was indicated between May 2008 and December 2014. The incidence of CPT-11-related cholinergic symptoms was investigated. Cholinergic symptoms were observed in 46 patients(75.4%), of whom 29(47.5%)showed Grade 2 or higher symptoms as follows: nasal discharge(47.5%), lacrimation(39.3%), nausea/vomiting(29.5%), and watery stool (26.2%). The results of the multivariate analysis showed that high-dose CPT-11 administration(150mg/m2)was a significant risk factor for the appearance of cholinergic symptoms and that PS 0 was a significant factor for reducing the onset of symptoms. It is important to adequately manage cholinergic symptoms, considering these clinical factors.

[Associations between Clinical Factors and Acute Renal Failure Due to Cisplatin Combination Chemotherapy for Lung Cancer].

In this study, we investigated the clinical factors associated with acute kidney injury (AKI) due to combination therapy with cisplatin (CDDP) for treating lung cancer. We classified cases according to the presence or absence of adequate hydration and magnesium(Mg)administered above the regulations of the registered regimen to evaluate the effect due to differences in hydration on AKI. We also investigated clinical factors before and after administration of CDDP in each case group, and examined their association with AKI. Seventy-four patients with lung cancer that were indicated for treatment with a CDDP combination regimen between December 2012 and April 2013 were studied. The patients whose conditions progressed to AKI of Bgrade 2 accounted for 0% (0/33) in the Mg administration group and 7.3%(3/41)in the Mg non-administration group. In particular, 2 cases of serious AKI (grade 4) were observed in the Mg non-administration without additional hydration group. When compared with other groups, a high antiemetic rate and favorable urine volume were observed in the Mg administration with additional hydration group. In the patients with AKI, many developed hyponatremia of Bgrade 3 within 1 week after administration of CDDP. Although Mg administration and ample hydration seem to be effective measures to deal with CDDP-caused AKI, comprehensive monitoring, including antiemesis therapy, after CDDP administration and correction of electrolytes is important.

[Risk factors for cardiotoxicity during fluorouracil and cisplatin combination chemotherapy].

We investigated the incidence of cardiovascular symptoms in patients treated with fluorouracil and cisplatin (FP) combination chemotherapy. Between April 2010 and March 2011, 61 patients were treated with FP therapy at the Department of Gastroenterology, Niigata Prefectural Cancer Center Hospital. Within 1 week of treatment and within the first or second course of therapy, six patients developed chest pain. To investigate the risk factors for cardiotoxicity following FP therapy, patients were divided into cardiotoxicity incidence and non-incidence groups. The prevalence of diabetes, hypertension, and heart disease was not significantly different between the two groups. Furthermore, serum sodium and potassium levels were not altered following FP therapy. Therefore, no definitive risk factors for cardiotoxicity were identified. These results suggest that while FP chemotherapy-induced nausea, vomiting, and renal damage are serious adverse effects, further attention should also be paid to the potential cardiotoxic effects of FP therapy.

Identification of inhibitory component in cinnamon--O-methoxycinnamaldehyde inhibits CYP1A2 and CYP2E1-.

The Cinnamomi Cortex and Ephedra Herba were found to more strongly inhibit aminopyrine N-demethylation in rat liver microsomes compared to other constituents included in Sho-seiryu-to. The component inhibiting drug oxidations catalyzed by CYP1A2 and CYP2E1 was isolated from Cinnamomi Cortex, and was identified as o-methoxycinnamaldehyde (OMCA). When phenacetin and 4-nitrophenol were used as probe substrates for CYP1A2 and CYP2E1, respectively, the OMCA was shown to be a competitive inhibitor against CYP1A2 while it was a mixed type inhibitor against CYP2E1. The inhibitory effect of OMCA on 4-nitrophenol 2-hydroxylation (K(i)=6.3 microM) was somewhat potent compared to that observed on phenacetin O-deethylation (K(i)=13.7 microM) in rat liver microsomes.