Pharmacogenomic study of gemcitabine efficacy in patients with metastatic pancreatic cancer: A multicenter, prospective, observational cohort study (GENESECT study).

BACKGROUND: Genetic polymorphisms of molecules are known to cause individual differences in the therapeutic efficacy of anticancer drugs. However, to date, germline mutations (but not somatic mutations) for anticancer drugs have not been adequately studied. The objective of this study was to investigate the association between germline polymorphisms of gemcitabine metabolic and transporter genes with carbohydrate antigen 19-9 (CA 19-9) response (decrease ≥50% from the pretreatment level at 8 weeks) and overall survival (OS) in patients with metastatic pancreatic cancer who receive gemcitabine-based chemotherapy. METHODS: This multicenter, prospective, observational study enrolled patients with metastatic pancreatic cancer patients who were receiving gemcitabine monotherapy or gemcitabine plus nanoparticle albumin-bound paclitaxel combination chemotherapy. Thirteen polymorphisms that may be involved in gemcitabine responsiveness were genotyped, and univariate and multivariate logistic regression analyses were used to determine the association of these genotypes with CA 19-9 response and OS. The significance level was set at 5%. RESULTS: In total, 180 patients from 11 hospitals in Japan were registered, and 159 patients whose CA 19-9 response could be assessed were included in the final analysis. Patients who had a CA 19-9 response had significantly longer OS (372 vs. 241 days; p = .007). RRM1 2464A>G and RRM2 175T>G polymorphisms suggested a weak association with CA 19-9 response and OS, but it was not statistically significant. COX-2 -765G>C polymorphism did not significantly correlate with CA 19-9 response but was significantly associated with OS (hazard ratio, 2.031; p = .019). CONCLUSIONS: Genetic polymorphisms from the pharmacokinetics of gemcitabine did not indicate a significant association with efficacy, but COX-2 polymorphisms involved in tumor cell proliferation might affect OS.

Chemotherapy-induced neutropenia as a prognostic factor in patients with extensive-stage small cell lung cancer.

PURPOSE: Chemotherapy-induced neutropenia (CIN) is a dose-limiting factor for cytotoxic chemotherapy, but recently, it was suggested that CIN contributes to prolonged survival. In this study, we examined the association between severe CIN and survival and determined whether CIN affected survival in patients with extensive-stage small cell lung cancer (ES-SCLC). METHODS: The medical records from 214 patients with ES-SCLC treated with etoposide or irinotecan in combination with cisplatin (EP/IP) between 2012 and 2016 were collected and retrospectively analyzed. Landmark analysis was performed at the end of cycle 4, and the relationship between severe CIN and survival was determined by a log-rank test. In addition, a multivariate analysis using the COX proportional hazard model was performed to identify independent predictive factors. The Landmark analysis included 102 patients in the IP group and 47 patients in the EP group. RESULTS: No significant difference was found between grades 0-3 and grade 4 neutropenia and overall survival (OS) in the EP group (P = 0.57). Contrariwise, for the IP patients, the median OS was 444 days for grades 0-3 and 633 days for grade 4 neutropenia, which was significantly longer for patients who developed grade 4 neutropenia (P = 0.03). Multivariate analysis adjusted for potential factors revealed that the development of grade 4 CIN was identified as a significant predictor of longer OS (hazard ratio [HR], 0.50; 95% confidence interval (CI), 0.28-0.87, P = 0.015). CONCLUSION: The results indicated that the development of severe CIN with IP therapy is associated with prolonged OS.

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.

Olanzapine 5 mg plus standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting (J-FORCE): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Olanzapine 10 mg added to standard antiemetic therapy including aprepitant, palonosetron, and dexamethasone has been recommended for the prevention of chemotherapy-induced nausea and vomiting. Guidelines suggest that a dose reduction to 5 mg should be considered to prevent sedation. In several phase 2 studies, olanzapine 5 mg has shown equivalent activity to olanzapine 10 mg and a favourable safety profile in relation to somnolence. We evaluated the efficacy of olanzapine 5 mg combined with standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting caused by cisplatin-based chemotherapy. METHODS: This was a randomised, double-blind, placebo-controlled, phase 3 study to evaluate the efficacy of olanzapine 5 mg with triplet-combination antiemetic therapy done in 26 hospitals in Japan. Key inclusion criteria were patients with a malignant tumour (excluding those with a haemopoietic malignancy) who were scheduled to be treated with cisplatin (≥50 mg/m2) for the first time, age between 20 and 75 years, and with Eastern Cooperative Oncology Group performance status of 0-2. Eligible patients were randomly assigned (1:1) to receive either oral olanzapine 5 mg or placebo once daily on days 1-4 combined with aprepitant, palonosetron, and dexamethasone (dosage based on the standard antiemetic therapy against highly emetogenic chemotherapy). Patients were randomly assigned to interventions by use of a web entry system and the minimisation method with a random component, with sex, dose of cisplatin, and age as factors of allocation adjustment. Patients, medical staff, investigators, and individuals handling data were all masked to treatment assignment. The primary endpoint was the proportion of patients who achieved a complete response, defined as absence of vomiting and no use of rescue medications in the delayed phase (24-120 h). All randomly assigned patients who satisfied eligibility criteria received a dose of cisplatin 50 mg/m2 or more, and at least one study treatment, were included in efficacy analysis. All patients who received any treatment in this study were assessed for safety. This study is registered at UMIN Clinical Trials Registry, number UMIN000024676. FINDINGS: Between Feb 9, 2017, and July 13, 2018, 710 patients were enrolled; 356 were randomly assigned to receive olanzapine and 354 were assigned to receive placebo. All eligible patients were observed 120 h after cisplatin initiation. One patient in the olanzapine group and three in the placebo group did not receive treatment and were excluded from all analyses. One patient in the olanzapine group discontinued treatment on day 1 and was excluded from the efficacy analysis. In the delayed phase, the proportion of patients who achieved a complete response was 280 (79% [95% CI 75-83] of 354 patients in the olanzapine group and 231 (66% [61-71] of 351 patients in the placebo group (p<0·0001). One patient had grade 3 constipation and one patient had grade 3 somnolence related to treatment in the olanzapine group. INTERPRETATION: Olanzapine 5 mg combined with aprepitant, palonosetron, and dexamethasone could be a new standard antiemetic therapy for patients undergoing cisplatin-based chemotherapy. FUNDING: Japan Agency for Medical Research and Development.

Genetic risk factors for chemotherapy-induced nausea and vomiting in patients with cancer receiving cisplatin-based chemotherapy.

PURPOSE: Younger age and female sex have already been well-known risk factors for chemotherapy-induced nausea and vomiting (CINV), and 30-50% of cancer patients still suffer from CINV. Genetic polymorphisms are suggested to influence antiemetic treatment response. METHODS: This study included a subset of patients previously enrolled in a randomised controlled trial; 156 patients were evaluated. This study aimed to evaluate the role of pharmacogenomic polymorphisms relevant to antiemetic response in patients with cancer receiving cisplatin-based chemotherapy. The study's efficacy endpoint was the proportion of patients with complete response (CR). The study endpoint was evaluated separately in the acute (CR0-24) and delayed (CR24-120) phases. Thirteen polymorphisms were genotyped, and the association of these genotypes with the efficacy of prophylactic antiemetics was then investigated. Confounding variables for the CR were identified using stepwise multivariate logistic regression analysis. Age and sex were included as independent variables by the forced-entry method, and the stepwise method was used to select the pharmacogenomic factors for inclusion as independent variables. RESULTS: Multivariate logistic regression analysis revealed that the ERCC1 8092AA (odds ratio [OR] = 11.25; 95% confidence interval [CI] 1.74-72.71; p = 0.011) and female sex (OR = 3.63; 95% CI 1.14-11.58; p = 0.029) were significant predictors of CR0-24. No significant association of CR24-120 with pharmacogenomic polymorphisms was found via multivariate logistic regression analysis. CONCLUSIONS: ERCC1 polymorphism influenced the extent of CINV control in patients receiving cisplatin-based chemotherapy. TRIAL REGISTRATION: Clinical trial information: UMIN 000009335.

A double-blind randomized phase II dose-finding study of olanzapine 10 mg or 5 mg for the prophylaxis of emesis induced by highly emetogenic cisplatin-based chemotherapy.

PURPOSE: The aim of this phase II study was to evaluate the efficacy and safety of two doses (10 and 5 mg) of olanzapine in combination with standard antiemetic treatment (aprepitant, palonosetron, and dexamethasone) for patients receiving highly emetogenic chemotherapy (HEC). METHODS: A multi-institutional, double-blind, randomized phase II, dose-finding study of olanzapine was performed in patients with a malignant solid tumor who were receiving HEC with cisplatin (≥ 50 mg/m2). Patients were randomly assigned either olanzapine 10 or 5 mg orally on days 1-4, combined with standard antiemetic treatment. The primary endpoint was a complete response (CR; no emesis and no use of rescue medications) in the delayed phase (24-120 h after the start of cisplatin treatment). RESULTS: 153 patients were randomized to the 10 mg group (n = 76) or the 5 mg group (n = 77). The CR rate in the delayed phase was 77.6% (80% CI: 70.3-83.8, P = 0.01) in the 10 mg group and 85.7% (80% CI: 79.2-90.7, P < 0.001) in the 5 mg group (P value for H 0: complete response rate ≤ 65%). The most common adverse event was somnolence, which had an incidence of 53.3 and 45.5% in the 10 and 5 mg olanzapine groups, respectively. CONCLUSIONS: Both doses of 10 and 5 mg olanzapine provided a significant improvement in delayed emesis. A dose of 5 mg olanzapine was determined as the recommended dose for a further phase III study based on higher CR and lower somnolence rates. CLINICAL TRIAL INFORMATION: UMIN000014214.

A Study on Drug Interaction between Warfarin and Capecitabine with Special Reference to the Co-Administered Term or the Discontinuation Term of Capecitabine.

We used the prothrombin time international normalized ratio(PT-INR)to investigate the change in degree and term of warfarin following co-administration and after discontinuation of capecitabine. In this study, approximately 3 years of medical records of 7 patients receiving co-administration therapy of warfarin and capecitabine were obtained from 4 hospitals. We observed daily increases in PT-INR values up to peak PT-INR levels following co-administration of warfarin and capecitabine. Interestingly, the peak PT-INR values of 4 of the patients remained remarkably high despite discontinuation of capecitabine. The peak PT-INR values for concomitant warfarin and capecitabine were attained after an average of 31.3 days of usage. When compared with the average PT-INR values attained before co-administration, the PT-INR values following co-administration significantly increased by 3 times (p<0.05). After discontinuation of capecitabine for an average of 15.1 days, i. e., for approximately 14 days, the PT-INR values returned to the PT-INR values attained prior to co-administration. These results suggest that capecitabine has influence on the anticoagulant effect of warfarin during not only the co-administered term but also the discontinuation term, and that this influence occasionally continues after discontinuation of capecitabine. These findings also suggest that a period of approximately 14 days after discontinuation is necessary for the interaction of capecitabine to dissipate and the PT-INR values to return the levels attained before receiving concomitant warfarin and capecitabine.

Predictors of Near-Infrared Spectroscopy-Detected Lipid-Rich Plaques by Optical Coherence Tomography-Defined Morphological Features in Patients With Acute Coronary Syndrome.

Background: Near-infrared spectroscopy (NIRS) provides the localization of lipid-rich components in coronary plaques. However, morphological features in NIRS-detected lipid-rich plaques (LRP) are unclear. Methods: A total of 140 de novo culprit lesions in 140 patients with the acute coronary syndrome (ACS) who underwent NIRS and optical coherence tomography (OCT) examinations for the culprit lesions at the time of percutaneous coronary interventions were investigated. We defined a NIRS-LRP as a lesion with a maximum lipid core burden index of 4 mm [LCBI4mm] > 500 in the culprit plaque. Clinical demographics, angiographic, and OCT findings were compared between the patients with NIRS-LRP (n = 54) vs. those without NIRS-LRP (n = 86). Uni- and multivariable logistic regression analyses were performed to examine the independent OCT morphological predictors for NIRS-LRP. Results: Clinical demographics showed no significant differences between the two groups. The angiographic minimum lumen diameter was smaller in the NIRS-LRP group than in the non- NIRS-LRP group. In OCT analysis, the minimum flow area was smaller; lipid angle, lipid length, the prevalence of thin-cap fibroatheroma, and cholesterol crystals were greater in the NIRS-LRP group than in the non-NIRS-LRP group. Plaque rupture and thrombi were more frequent in the NIRS-LRP group, albeit not significant. In a multivariable logistic regression analysis, presence of thin-cap fibroatheroma [odds ratio (OR): 2.56; 95% CI: 1.12 to 5.84; p = 0.03] and cholesterol crystals (OR: 2.90; 95% CI: 1.20 to 6.99; p = 0.02) were independently predictive of NIRS-LRP. Conclusions: In ACS culprit lesions, OCT-detected thin-cap fibroatheroma and cholesterol crystals rather than plaque rupture and thrombi were closely associated with a great lipid-core burden.

[Clinical evaluation of calculating carboplatin dosage using Japanese equation for estimating GFR for gynecologic cancer].

Glomerular filtration rate (GFR) is an important factor when considering carboplatin dosage adjustment. The Japanese equation for estimating GFR (eGFR) was recommended as a guideline for evaluating GFR in 2009 by The Japanese Society of Nephrology. However, benefits in the field of cancer chemotherapy with the use of eGFR have not yet been shown. To clarify the clinical benefits of eGFR, we investigated the renal function of 100 patients with gynecologic cancer who were treated with carboplatin from 2003 through 2009, and the carboplatin dosage was calculated by the Calvert formula in which eGFR was substituted for GFR. To predict the clinical benefit on the basis of carboplatin dosage using eGFR, we retrospectively divided the patients into two groups so that carboplatin dosage was within dosage in using eGFR and one was not. We compared response rates and adverse effects of the two groups. Renal function using eGFR was lower than renal function calculated by using the other formulae. Carboplatin dosage using eGFR was significantly lower than the dosage calculated with the other formulae (p<0.01). Moreover, the patients group actually, administered the dosage calculated by eGFR showed less side effects than the group of patients not treated this way, but the efficacy did not change. Thus, using eGFR in planning carboplatin dosage suggested clinical application to patients with Japanese gynecologic cancer.

Coronary spasm and optical coherence tomography defined plaque erosion causing ST-segment-elevation acute myocardial infarction in a patient with COVID-19 pneumonia.

An 84-year-old man with coronavirus disease 2019 pneumonia developed ST-segment-elevation myocardial infarction and was brought to the catheterization laboratory. His angiogram showed a haziness in distal right coronary artery, and optical coherence tomography (OCT) exhibited vascular spasm and OCT-defined plaque erosion, which were thought to be the causes of non-obstructive myocardial infarction. .

Potentially harmful excipients in neonatal medications: a multicenter nationwide observational study in Japan.

BACKGROUND: A multicenter investigation of neonate exposure to potentially harmful excipients (PHEs) in neonatal intensive care units (NICUs) in Japan has not been conducted. METHODS: A multicenter nationwide observational study was conducted. Neonate patient demographic data and information on all medicines prescribed and administered during hospitalization on 1 day between November 2019 and March 2021 were extracted from the medical records. Nine PHEs, paraben, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol, ethanol, benzalkonium chloride, and aspartame, were selected. PHEs were identified from the package insert and the Interview Form. The quantitative daily exposure was calculated if quantitative data were available for each product containing the PHE. RESULTS: Prescription data was collected from 22 NICUs in Japan. In total, 343 neonates received 2360 prescriptions for 426 products containing 228 active pharmaceutical ingredients. PHEs were found in 52 (12.2%) products in 646 (27.4%) prescriptions for 282 (82.2%) neonates. Benzyl alcohol, sodium benzoates, and parabens were the most common PHEs in parenteral, enteral, and topical formulations, respectively. Quantitative analysis showed that 10 (10%), 38 (42.2%), 37 (94.9%), and 9 (39.1%) neonates received doses exceeding the acceptable daily intake of benzyl alcohol, polysorbate 80, propylene glycol, and sorbitol, respectively. However, due to the lack of quantitative information for all enteral and topical products, accurate daily PHE exposure could not be quantified. CONCLUSIONS: Neonates admitted to NICUs in Japan were exposed to PHEs, and several of the most commonly prescribed medicines in daily clinical practice in NICUs contained PHEs. Neonate PHE exposure could be reduced by replacing these medicines with available PHE-free alternatives.