Fast and Ultrasensitive Glycoform Analysis by Supercritical Fluid Chromatography-Tandem Mass Spectrometry.

The glycoform of a therapeutic monoclonal antibody (mAb) has a significant impact on its effector function as well as its safety and pharmacokinetics. Glycoform heterogeneity is influenced by various factors, including the producing cells and cell culture processes. Therefore, accurate glycoform characterization is essential for drug design, process optimization, manufacturing, and quality control of therapeutic mAbs. In this study, we developed a fast, quantitative, and highly sensitive analytical platform for glycan profiling by supercritical fluid chromatography-tandem mass spectrometry (SFC-MS/MS) and applied the technique to the glycan structural analysis of mAbs. To achieve both the highest sensitivity and the most comprehensive glycan profiling, we integrated our energy-resolved oxonium ion monitoring (Erexim) method with SFC-MS to construct a new SFC-Erexim technology. An 8 min analysis of bevacizumab, nivolumab, ramucirumab, rituximab, and trastuzumab by SFC-Erexim detected a total of 102 glycoforms, with a detection limit of 5 attomoles. The dynamic range of glycan abundance was over 6 orders of magnitude for bevacizumab analysis by SFC-Erexim compared to 3 orders of magnitude for conventional fluorescence HPLC analysis. This method revealed the glycan profile characteristics and lot-to-lot heterogeneity of various therapeutic mAbs. We were also able to detect a series of structural variations in pharmacologically important glycan structures. The SFC-MS-based glycoform profiling method will provide an ideal platform for the in-depth analysis of precise glycan structure and abundance.

[Evaluation of Neutropenia and Usages of Antihypertensive Drugs in Patients Treated with Ramucirumab plus Paclitaxel Therapy].

Hypertension is one of the main side effects of ramucirumab(RAM)plus paclitaxel(PTX)therapy. Although dihydropyridine calcium channel blockers(D-CCBs)are considered to cause drug-drug interactions with PTX based on the inhibition of cytochrome P450, D-CCBs are often administered to patients receiving RAM plus PTX therapy in clinical practice. We retrospectively studied the actual usage of antihypertensive drugs in 133 advanced or recurrent gastric cancer patients who received RAM plus PTX therapy. Antihypertensive drugs were administered to 34(25.6%)patients. Among them, 13 (38.2%)received antihypertensive drugs during the first course, and 19(55.9%)received D-CCBs. We also investigated whether D-CCBs affect the expression of Grade 3 or higher neutropenia caused by PTX. Results of multivariate analysis indicated that D-CCBs did not increase the risk of neutropenia caused by PTX.

The Combined Use of 5 or More Drugs Is a Factor Related to Lower Adherence to S-1 in S-1 and Oxaliplatin Treatment for Advanced Gastric Cancer.

S-1 plus oxaliplatin (SOX) is an established treatment for advanced gastric cancer. S-1 adherence is the key to successful SOX treatment. This study focused on S-1 adherence by evaluating real-world adherence to S-1 and investigating factors related to decreased S-1 adherence. This study included cases treated between August 1, 2014 and October 12, 2016 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. The S-1 adherence rate per cycle was defined as the number of times a patient took S-1/28. In this study, adherence to S-1 was assessed through pill counts and by asking the patient about the reason for non-adherence at a pharmaceutical outpatient clinic. Univariate and multivariate analyses were performed to investigate factors influencing lower adherence. This analysis included 116 patients evaluated for adherence to S-1 on SOX treatment. The median rate of adherence to S-1 was 92.8% in the first cycle and 90.5% in the seventh cycle. The median relative dose intensity of S-1 was 84.6%. In terms of reasons for nonadherence, patients most commonly cited nausea/vomiting (43.7%), diarrhea (20.8%), missed dose (11.8%), and fever (8.1%). Logistic regression analysis was performed using the most appropriate regression equation, and a significant association was detected with 1 factor, number of combined drugs ≥5 (odds ratio (OR) = 2.50; 95% confidence interval (CI), 1.04-6.03, p = 0.04). Eliminating unnecessary concomitant medications helps maintain proper adherence to S-1 in SOX treatment.

Occurrence of Infusion-Related Reactions due to Obinutuzumab Therapy for Follicular Lymphoma.

BACKGROUND: Obinutuzumab is used to treat follicular lymphoma in Japan. Its characteristic adverse event is infusion- related reactions(IRRs). Although interruption of administration improves many IRRs, serious symptoms can occur; thus, timing the interruption to correspond with the onset of these symptoms is necessary. However, the specific symptoms and timing of IRRs caused by obinutuzumab remain unclear. Therefore, the purpose of this study was to clarify the specific symptoms and timing of the onset of IRRs with obinutuzumab treatment. METHODS: Thirty patients were administered obinutuzumab for one year from October 2018 to September 2019. The frequency of IRRs, expression time, severity, symptoms, and correspondence were investigated. RESULTS: IRRs occurred in 13 patients(43.3%), and all occurred after the first dosing. In 9 of 13 cases(69.2%), IRRs occurred within 90 min of the first dosage. Grade 3 symptoms were expressed in 1 of 13 cases (7.7%). The symptoms of IRRs were throat discomfort, breathing difficulty, skin rash, chills, and fever. CONCLUSIONS: Most IRRs due to obinutuzumab occurred within 90 min of the first dosage. They were mostly Grade 2 or lower, and the frequency of serious IRRs was low. Thus, careful observation of symptoms during treatment with obinutuzumab is necessary.

Association of Immune-Related Adverse Events with Pembrolizumab Efficacy in the Treatment of Advanced Urothelial Carcinoma.

PURPOSE: Immune-related adverse events (irAEs) have been associated with the efficacy of programmed cell death protein 1 (PD-1) inhibitors in patients with urothelial cancer. We therefore evaluated the relationship between irAEs and pembrolizumab efficacy in urothelial cancer patients. METHODS: Patients with urothelial cancer who were treated with pembrolizumab in a second-line setting or later between January 2018 and December 2018 were identified by reviewing their medical records from the Cancer Institute Hospital, Japanese Foundation for Cancer Research. Data were updated as of December 31, 2018. Kaplan-Meier curves for overall survival (OS) and time to treatment failure (TTF) according to irAE grade were evaluated using the log-rank test. Risk factors for exacerbation of irAEs were also evaluated with multivariate analysis. RESULTS: In this retrospective study, 43 patients received pembrolizumab. We identified irAEs in 22 of the 43 patients (51.2%), including 11 patients (25.6%) with grade 2 or 3 events. In patients with irAE grade 0 or 1, median TTF was 127 days, and median OS was 160 days according to the Kaplan-Meier method. On the other hand, in patients with irAE grade ≥2, median TTF and OS were not reached. Multivariate analysis also revealed that risk factors for exacerbation of irAEs (to grade ≥2) were positively associated with lymphocyte count at baseline (>2,000/µL) before pembrolizumab treatment (p = 0.021). CONCLUSIONS: Development of irAEs was associated with survival outcome of pembrolizumab treatment in patients with advanced urothelial cancer.

[Effect of the Antiemetic Drug Olanzapine on Blood Sugar Levels in Patients Treated with Adjuvant or Neoadjuvant Chemotherapy for Breast Cancer].

This retrospective study aimed to evaluate the effect of the antiemetic drug olanzapine(OLZ)on blood sugar levels in patients treated with adjuvant or neoadjuvant chemotherapy(AC: doxorubicin plus cyclophosphamide or CEF: cyclophosphamide plus epirubicin plus fluorouracil) for breast cancer. Here, we evaluated the frequency of diabetes(postprandial blood sugar: PBS≥200 mg/dL)and the change in PBS in 149 patients who were prescribed OLZ between September 2016 and August 2017 at our hospital. No diabetic patients were identified during the observation period(median: 3 cycles of chemotherapy). Among the 95 patients with more than 2 PBS readings, no difference was observed in the incidence of increased PBS, regardless of the diabetic risk, before and after OLZ administration. This study therefore found that the short term use of OLZ as an antiemetic had little effect on PBS, suggesting that it can be used safely during treatment with AC or CEF.

Association of Hand-Foot Skin Reaction with Regorafenib Efficacy in the Treatment of Metastatic Colorectal Cancer.

PURPOSE: Hand-foot skin reaction (HFSR) can deteriorate quality of life in patients receiving regorafenib. Cutaneous toxicity is a main adverse effect of multikinase inhibitors and has also been associated with clinical outcome. This study assessed the association between the antitumor efficacy of regorafenib and HFSR in patients with metastatic colorectal cancer (mCRC). METHODS: Patients who received regorafenib at 160 mg/day during the first 3 weeks of each 4-week cycle were divided into subgroups based on whether they developed HFSR between May 2013 and October 2015. Estimates of overall survival and progression-free survival were calculated using the Kaplan-Meier method. RESULTS: Ninety-seven patients received at least one dose of regorafenib in this retrospective study. Of these patients, 81.4% (n = 79) experienced HFSR of any grade, and 34.0% (n = 33) had grade 3 HFSR. Among those patients with HFSR at any time during the study, 68.0% (n = 66) underwent the first HFSR event (any grade) during cycle 1. Both overall survival and progression-free survival were improved in patients who had HFSR grade ≥2 at any time compared with those who had HFSR grade ≤1. Multivariate logistic regression analysis revealed a history of HFSR grade ≥2 induced by capecitabine as a significant risk factor for severe HFSR (grade ≥2). CONCLUSIONS: Patients with mCRC treated using regorafenib who experienced severe HFSR showed better overall survival than patients without severe HFSR. Severe HFSR may offer an early surrogate marker for the efficacy of regorafenib in patients with mCRC.

Risk factors associated with chemotherapy-induced nausea and vomiting in the triplet antiemetic regimen including palonosetron or granisetron for cisplatin-based chemotherapy: analysis of a randomized, double-blind controlled trial.

PURPOSE: The triplet antiemetic regimen is recommended for cisplatin-based highly emetogenic chemotherapy, in the current guidelines for antiemetic prophylaxis. Although risk factors related to chemotherapy-induced nausea and vomiting (CINV) have been identified by several prior studies, there are only few studies evaluating risk factors associated with the prophylactic triplet antiemetic therapy, particularly in palonosetron use. The present study aimed to reveal the risk factors related to CINV development in patients receiving cisplatin and to compare CINV risk factors between palonosetron and granisetron use. METHODS: In total, 825 patients in a phase III trial receiving palonosetron with graniestron were evaluated. Multivariate logistic regression models were used to predict risk factors associated with CINV development. Additionally, risk factors associated with CINV development were separately evaluated in each treatment group. RESULTS: Multivariate analysis of the entire study group revealed that sex, age, cisplatin dose, and granisetron use were significant and independent factors affecting CINV development in the overall phase. Similarly, sex and age were risk factors for CINV in both treatment groups. Kaplan-Meier curves classified by each treatment group showed no significant difference between the groups among patients without any risk factors for CINV (P = 0.353). Conversely, complete response rates for patients with at least one risk factor were higher in patients receiving palonosetron (P = 0.049). CONCLUSIONS: This analysis revealed the importance of previously reported CINV risk factors when using triplet antiemetics. Palonosetron might be preferred for patients with at least one risk factor.

Drug interactions between tyrosine kinase inhibitors (gefitinib and erlotinib) and warfarin: Assessment of international normalized ratio elevation characteristics and in vitro CYP2C9 activity.

BACKGROUND: Elevation of the international normalized ratio and bleeding complications has been reported in patients taking warfarin concomitantly with tyrosine kinase inhibitors such as gefitinib and erlotinib. OBJECTIVE: To assess the frequency, degree, and onset of international normalized ratio elevation in patients receiving warfarin with gefitinib or erlotinib, and changes in vitro cytochrome P450 2C9 activity. METHODS: This retrospective, single-center, observational study compared international normalized ratio values during the treatment with warfarin in the absence and presence of the tyrosine kinase inhibitors, gefitinib, and erlotinib. In addition, the inhibitory effect of tyrosine kinase inhibitors on cytochrome P450 2C9 activity was screened in an in vitro study. RESULTS: Compared with international normalized ratio at the baseline significant (P < 0.05) international normalized ratio elevations were observed in the majority of the patients (5/6 patients with gefitinib, 83.3%; 6/7 patients with erlotinib, 85.7%) during concurrent therapy. The international normalized ratio was increased 1.8- and 1.6-fold relative to the baseline value, on median, in the presence of gefitinib and erlotinib, respectively, and the onset of international normalized ratio elevation was observed at a median of seven days and nine days, respectively. In vitro (S)-warfarin 7-hydroxylation activity was inhibited by 36% in the presence of 1 µM gefitinib and 27% by 10 µM erlotinib, which are comparable to the steady-state plasma levels of these tyrosine kinase inhibitors after standard dosing. CONCLUSION: In most patients, international normalized ratio elevation was observed within two weeks of the start of concomitant therapy with warfarin and gefitinib or erlotinib. To avoid excessive anticoagulant response by warfarin, international normalized ratio should be carefully monitored weekly and dosage adjustment of warfarin might be recommended during the first month after the start of concurrent tyrosine kinase inhibitor therapy.

[Effects of Tyrosine Kinase Inhibitors on Control of PT-INR in Patients Receiving Warfarin].

Few studies have evaluated the influence of anticancer drugs on the anticoagulation response to warfarin(WF). This retrospective, single-center, observationalstudy evaluated the changes in prothrombin time-internationalnormal ized ratio (PT-INR)in patients receiving a combination of WF and anticancer drugs. We compared(a)PT-INR changes between groups receiving WF and concomitantly started on either tyrosine kinase inhibitors(TKI)(WF+TKI group: n=14)or anticancer drugs other than TKI(WF+non-TKI group: n=20)and(b)PT-INR changes between groups that were started on WF concomitantly while receiving either TKI(TKI+WF group: n=16)or anticancer drugs other than TKI(non-TKI+WF group: n=13). (a)PT-INR changes were significantly larger in the WF+TKI group than in the WF+non-TKI group(2.23 vs 0.42, p<0.001). In the WF+TKI group, the WF dose was reduced after all 14 patients(100.0%)showed increased PT-INR.(b)PT-INR changes during the WF induction period were significantly larger in the TKI+WF group than in the non-TKI+WF group(2.18 vs 0.68, p<0.001). In the TKI+WF group, the WF dose was reduced after 12 patients(75.0%)showed increased PT-INR. It might be necessary to consider a reduction in WF dose when WF is administered in combination with TKIs.

[Effects of Seven Tyrosine Kinase Inhibitors on the Anticoagulation Activity of Warfarin].

Several studies have reported increased anticoagulation effect of warfarin(WF)when combined with tyrosine kinase inhibitors(TKIs), such as gefitinib and erlotinib. However, effects of TKIs other than gefitinib and erlotinib on the anticoagulation effect of WF have not been clarified. To assess the degree and onset of prothrombin time-international normalized ratio (PT-INR)elevation and changes in WF daily doses in patients additionally receiving TKIs, this retrospective, single-center observational study compared PT-INR values and WF daily doses during WF treatment in the absence and presence of TKIs. Seven different TKIs(afatinib, alectinib, axitinib, crizotinib, pazopanib, regorafenib, and vandetanib)were prescribed during treatment with WF of venous thromboembolism in 10 cancer patients. Compared to baseline PT-INR, significant PT-INR elevations were observed in all patients during the combination therapy. The median PT-INR increased 1.6-fold from the baseline in the presence of TKIs(p<0.01), and the onset of PT-INR elevation was observed at a median of 18 days. As all patients receiving WF with the 7 TKIs showed PT-INR elevation, enhancement of the anticoagulation effect of WF in the presence of TKIs appears to be highly frequent. PT-INR should be carefully monitored, and adjusting the WF dosage may become necessary during the WF and TKI combination therapy.

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.

[Safety Profile of the Combination of Prophylactic Pegfilgrastim and Cabazitaxel for Japanese Patients with Castration Resistant Prostate Cancer].

Cabazitaxel, which is a novel semi-synthetic anti-cancerous agent, is newly approved for the treatment of metastatic castration resistant prostate cancer(CRPC). The main dose-limiting toxicity is considered to be febrile neutropenia(FN). In this study, we retrospectively investigated the safety profiles of Japanese patients during cabazitaxel therapy. From September 2014 to August 2016, 17 patients initiated receiving cabazitaxel therapy in our institution. Prophylactically, pegfilgrastim was administered to all patients. Among 17 patients, 5 patients(29.4%)developed FN. Four of these patients(80%)developed FN in the first cycle and could continue the cabazitaxel therapy with dose modification, whereas 1 patient(20%)developed FN leading to septic shock in the 8th cycle. Although he recovered after appropriate medical treatment, he discontinued the cabazitaxel therapy. Regarding non-hematological adverse events, no unknown adverse events were observed. The most frequently observed adverse event was back pain(n=4, 23.5%). There was no influence on the continuation of treatment. Treatment discontinuation due to adverse events was observed in 1 patient(5.9%). Due to the prophylactic pegfilgrastim in combination, the occurrence rate of FN seemed to decrease. However, we must remember that FN is still frequently expressed even under the prophylactic pegfilgrastim.

Self-Reported Adherence to Trifluridine and Tipiracil Hydrochloride for Metastatic Colorectal Cancer: A Retrospective Cohort Study.

BACKGROUND: A novel oral agent that consists of trifluridine and tipiracil hydrochloride (TFTD) has been established as salvage-line treatment for metastatic colorectal cancer (mCRC). Adherence to TFTD is crucial to maintaining appropriate curative effects. This study sought to clarify adherence to TFTD and identify candidate factors deteriorating adherence at our institution. METHODS: A total of 50 consecutive mCRC patients who received TFTD monotherapy between June 1, 2014 and July 31, 2015 were analyzed in this study. Adherence to TFTD was checked by pharmacists using a self-reported treatment diary and interviewing nonadherents at a pharmaceutical outpatient clinic. The adherence rate was defined as the number of patient intakes per 20 scheduled intakes in one cycle. We retrospectively surveyed the factors from the electronic patient record associated with reduced adherence. We measured relative dose intensity, defined as the dose intensity divided by the initial dose (each in milligrams per square meter per week). RESULTS: Patient characteristics were as follows: males/females, 20/30; median age, 61 years (range, 34-83 years); performance status 0/1, 37/13. Median relative dose intensity of TFTD was 91.0%. Adherence rates were 95.0% for the first cycle of TFTD, 97.3% for the second cycle, 98.0% for the third cycle, and 98.2% for the fourth cycle. Factors associated with deteriorated adherence to TFTD were nausea/vomiting/decreased appetite (27.1%, 23 instances), pain (25.9%, 22 instances), neutropenia (11.8%, 10 instances), and missed dose (4.7%, 4 instances). Increased nonadherence to TFTD was associated with Eastern Cooperative Oncology Group performance status 1, while increased TFTD adherence in the first cycle was associated with prior regimens ≥4. CONCLUSIONS: The high frequency of treatment-related gastrointestinal disorder is the main factor affecting adherence to TFTD. Intensive supportive care in the management of these symptoms could assist adequate adherence to TFTD in mCRC patients.

Risk Factors Exacerbating Hand-Foot Skin Reaction Induced by Capecitabine plus Oxaliplatin with or without Bevacizumab Therapy.

BACKGROUND: Capecitabine plus oxaliplatin (CapeOx) ± bevacizumab therapy is associated with a high incidence of hand-foot skin reaction (HFSR), hindering treatment. However, timing of onset and risk factors remain unclear. OBJECTIVE: This study examined the development of HFSR and risk factors for its exacerbation to a serious condition in CapeOx ± bevacizumab therapy. METHODS: We retrospectively examined patients with colorectal cancer receiving CapeOx ± bevacizumab therapy between October 1, 2009, and March 31, 2012. The observation period was defined as lasting until completion of 8 cycles. The relationship between cumulative dose of capecitabine and cumulative proportion of patients developing HFSR was evaluated by Kaplan-Meier methods. Risk factors for exacerbation of HFSR to a serious condition were assessed by multiple logistic regression. RESULTS: Data for 203 patients were analyzed. For patients treated at cumulative capecitabine doses of 100 000 mg/m(2) and 200 000 mg/m(2), Grade 1 HFSR occurred in ≥80% and ≥90%, respectively, and moderate-to-severe HFSR (Grade 2+) occurred in ≥10% and ≥20%, respectively. Multivariate analysis showed significant associations with diabetes (odds ratio [OR] = 4.79; 95% confidence interval [CI] = 1.86-12.34; P = 0.001), concomitant use of bevacizumab (OR = 6.01; 95% CI = 2.20-16.41; P = 0.001), history of fluorinated pyrimidine administration (OR = 2.42; 95% CI = 1.10-5.33; P = 0.027), and early onset (within 21 days) of Grade 1 HFSR (OR = 3.78; 95% CI = 1.64-8.70; P = 0.001). CONCLUSIONS: HFSR in CapeOx therapy is a cumulative toxicity and risk of exacerbation to a serious condition increases with diabetes, concomitant use of bevacizumab, history of fluorinated pyrimidine administration, and onset of Grade 1 HFSR within 21 days.

Association between pazopanib exposure and safety in Japanese patients with renal cell carcinoma or soft tissue sarcoma.

The safety and effectiveness of pazopanib are related to plasma trough concentrations in renal cell carcinoma (RCC); however, data on pazopanib plasma trough concentrations with soft tissue sarcoma (STS) are limited. This study investigated the relationship between plasma trough concentrations and pazopanib safety in 45 Japanese patients with RCC or STS. Among the 33 patients included, the median pazopanib trough concentration was 37.5 (range, 12.1-67.6) µg/mL, which was not significantly different between Japanese RCC and STS patients. The plasma trough concentrations showed significant and positive correlations with aspartate aminotransferase and alanine aminotransferase values in blood samples taken for pharmacokinetic measurements after the administration. The incidence of pazopanib treatment discontinuation were significantly higher in RCC patients (p = 0.027). The primary reason for treatment discontinuation was hepatic dysfunction (5/6, 83.3%). Furthermore, this study revealed that pazopanib trough concentration was affected significantly by proton pump inhibitors but not by histamine 2-receptor blockers. In conclusion, the observed pazopanib trough levels and their safety in the Japanese RCC and STS populations in this study were similar to those of the global population. This is the first study to correlate the hepatotoxicity and pharmacokinetic property of pazopanib plasma trough levels by comparing Japanese patients with RCC or STS.

Factors exacerbating peripheral neuropathy induced by paclitaxel plus carboplatin in non-small cell lung cancer.

No established supportive therapy to prevent and treat chemotherapy-induced peripheral neuropathy (PN) is available. Minimizing the severity of PN is therefore critical in clinical use. We aimed to determine when and how often PN occurs in association with paclitaxel plus carboplatin (PC therapy), a regimen used to treat non-small cell lung cancer, and factors that exacerbate this condition. Patients who received PC therapy for non-small cell lung cancer at the Japanese Foundation for Cancer Research, Cancer Institute Hospital, between May 20, 2009, and November 30, 2010, were included. PN was evaluated by the study pharmacist using specific questions based on the Common Terminology Criteria for Adverse Events Version 3.0. Univariate analysis was used to compare a group with no, Grade 1, or Grade 2 PN (non-serious) and a group with Grade 3 PN (serious). Analyses were conducted using the Cox proportional hazard model with patient characteristics having p < or = 0.20 when assessed as independent variables. Of 50 patients, 38 (76.0%) developed PN by day 6 of the first course of anticancer treatment. Grade 3 PN had an incidence of 25.0% in the fourth course. In multivariate analysis with the Cox proportional hazard model, pack-year [hazard ratio = 1.029; 95% confidence interval (CI): 1.009-1.050, p = 0.005] and creatinine clearance (hazard ratio = 0.957; 95% CI: 0.920-0.996, p = 0.031) were significant factors. A high pack-year and a low creatinine clearance exacerbated PN in patients treated with PC. PN must be carefully evaluated in patients with exacerbating factors.

Paclitaxel increases high voltage-dependent calcium channel current in dorsal root ganglion neurons of the rat.

Peripheral neuropathic pain is a serious side effect of paclitaxel treatment. However, the mechanism of this paclitaxel-induced neuropathic pain is unknown. In this study, we investigated the effects of paclitaxel on the voltage-dependent calcium channel (VDCC) current in rat dorsal root ganglion (DRG) neurons using the whole-cell patch clamp technique. Behavioral assessment using von Frey filament stimuli showed that 2 and 4 mg/kg paclitaxel treatment induced mechanical allodynia/hyperalgesia. Paclitaxel-induced mechanical hyperalgesia was significantly inhibited by gabapentin (100 mg/kg). Using the patch clamp method, we observed that paclitaxel (4 mg/kg) treatment significantly increased the VDCC current in small- and medium-diameter DRG neurons. Moreover, paclitaxel-induced increase in the VDCC current in medium-diameter DRG neurons was completely inhibited by 10 and 100 µM gabapentin. Similar effects in small-diameter DRG neurons were only seen with 100 µM gabapentin. Western blotting revealed that paclitaxel increased protein levels of the VDCC subunit α2δ-1 (Ca(v)α2δ-1) in DRG neurons. Immunohistochemistry showed that paclitaxel treatment increased Ca(v)α2δ-1 protein expression in DRG neurons. Thus, paclitaxel treatment increases the VDCC current in small- and medium-diameter DRG neurons and upregulates Ca(v)α2δ-1. The antihyperalgesic action of gabapentin may be due to inhibition of paclitaxel-induced increases in the VDCC current in DRG neurons.

Safety evaluation of fixed-dose nivolumab in patients with gastric cancer.

Background and Aims: This study aimed to examine the safety of fixed-dose nivolumab. Methods: We retrospectively reviewed the medical records of 113 Japanese patients with gastric cancer who were previously treated with cytotoxic chemotherapy and initiated nivolumab. The endpoints were the incidence of Grade 2 or higher immune-related adverse events (irAEs) in the conventional dose (3 mg/kg) and fixed-dose groups (240 mg). Results: The incidence rates of irAEs in the conventional-dose and fixed-dose groups were 29.9% and 19.4%, respectively, and the rates of Grade 2 or higher irAEs were 23.3% and 19.4%, respectively, with no significant difference between the two groups, suggesting that nivolumab at 240 mg is as safe as the 3 mg/kg dose. Conclusion: This is the first report on the safety of nivolumab at 240 mg in Japanese patients.

Multicenter study for environmental and biological monitoring of occupational exposure to cyclophosphamide in Japan.

PURPOSE: A multicenter field survey of environmental contamination and exposure of healthcare professionals to anticancer drugs were performed. SETTING: Three university hospitals, one cancer specialty hospital and two corporate hospitals from across Japan. METHOD: The environmental contamination with cyclophosphamide (CP) was investigated. A wipe examination was performed at six sites apiece in two divisions. The urinary excretion of the CP over 24 h was determined. The subjects of the survey included physicians, pharmacists, and nurses, for a total of seven at each facility irrespective of job title. The wipe samples were collected at 12 sites within two divisions at each facility. For the exposure survey, the total urine volume was determined, and a portion of the urine sample was then collected from each participants at each facility. Urine was collected for 24 h. The samples were determined by using the GC-MS method. RESULTS: Wipe examination: contamination with CP was identified at 50% of the sites. The concentration was high (CP > 1.00 ng/cm(2)) in the general environment in two hospitals and in the safety cabinet in one hospital. In the survey for the exposure of staff to anticancer drugs, 276 samples were obtained from 41 healthcare professionals. CP was detected in 90 samples obtained from 23 subjects. The amount of exposure was greatly different among the facilities. The urinary excretion of CP per subject was between 2.7 and 462.8 ng/24 h. The range of urinary excretion for each hospital was between 4.6 and 211.2 ng/24 h.