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.

Cancer-Chemotherapy-Related Regimen Checks Performed by Pharmacists of General Hospitals Other than Cancer Treatment Collaborative Base Hospitals: A Multicenter, Prospective Survey.

Although prescription review is an important role for pharmacists in anticancer drug therapy, there are no guidelines in Japan that specify what pharmacists should check for in chemotherapy regimens. This prospective multicenter survey aimed to investigate the implementation of chemotherapy regimen checks by pharmacists in general hospitals by focusing on 19 recommended confirmation items designed to enhance chemotherapy safety. This study involved 14 hospitals within the National Hospital Organization in different regions of Japan. The top five cancers in Japan (gastric, colorectal, lung, breast, and gynecological) were targeted and specific chemotherapy regimens were analyzed. This study assessed the amount of time required for regimen checks, the number of confirmation items completed, the number and the content of inquiries raised regarding prescriptions, and the pharmacists' opinions using a questionnaire that had a maximum score of 10 points. Pharmacists checked 345 and 375 chemotherapies of patients in the control group (CG) and recommended items group (RIG), respectively. The mean time periods required for completing a chemotherapy regimen check were 4 min and 14 s (SD ±1 min and 50 s) and 6 min and 18 s (SD, ±1 min and 7 s) in the CG and RIG, respectively. The mean of the recommended items for the CG = 12.4 and for the RIG = 18.6. The items that the pharmacists did not confirm included urine protein (sixty-nine cases, 18.4%), allergy history (four cases, 1%), previous history (two cases, 0.5%), and a previous history of hepatitis B virus (sixty-nine cases, 18.4%). The number of inquiries for a doctor's prescription order was higher in the RIG than in the CG (41 vs. 27 cases). This multicenter survey demonstrated the potential effectiveness of implementing 19 recommended confirmation items in the regimen checks by pharmacists in general hospitals other than cancer treatment collaborative base hospitals.

Promotion of proper use of anti-SARS-CoV-2 drugs and SARS-CoV-2 vaccines by hospital pharmacists and establishment of an adverse drug reaction reporting system.

Newly developed anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs are being rapidly approved in countries worldwide. These new drugs are being approved after testing with a limited number of cases, and in real-world clinical practice, unknown and potentially serious adverse events that could not be detected in clinical trials may emerge. Accordingly, in the event of an adverse drug reaction for which a causal relationship with these new drugs cannot be ruled out, it is vital to promptly report the details of the case to the regulatory authorities. To date, through close cooperation between physicians and pharmacists, we have reported four cases of adverse drug reactions for which a causal relationship to anti-SARS-CoV-2 drugs cannot be ruled out. Herein, we introduce safety measures taken by pharmacists when using these new drugs in the hospital, and a system for reporting to the regulatory authorities when adverse events occur.

Importance of Compliance With Guidelines for the Prevention of Varicella-Zoster Virus Reactivation in Multiple Myeloma.

BACKGROUND/AIM: The importance of compliance with National Comprehensive Cancer Network (NCCN) guidelines for preventing varicella-zoster virus reactivation (VZVr) in multiple myeloma (MM) in a clinical setting has not been well investigated. PATIENTS AND METHODS: We retrospectively studied the clinical characteristics and outcomes of 118 patients with MM treated with proteasome inhibitors. RESULTS: Thirty-nine episodes of VZVr were observed in 37 patients (VZVr group). The proportion of prophylactic antiviral prescriptions and compliance with antiviral prophylaxis based on the NCCN Clinical Practice guidelines was 76% and 30% in the VZVr group, and 88% and 74% in the non-VZVr group, respectively. Multivariate analysis showed that compliance with the NCCN guidelines was the only independent risk factor for VZVr (p=0.0017). CONCLUSION: It is important that prophylactic antivirals are prescribed for an appropriate duration of time to prevent the reactivation of VZV in compliance with existing guidelines.

Contamination of lenalidomide on blister packages after administration and its exposure countermeasures.

BACKGROUND: Reliable exposure control measures are needed to avoid occupational exposures from hazardous drugs. However, there is little information on blister packages concerning exposure. We investigated the contamination and exposure control methods of lenalidomide. MATERIALS AND METHODS: Nine facilities involved with the RevMate program (the Japanese REMS program) participated in this study. Blister packages (10 capsules/ sheet, no cuts) were collected from each institution after the administration of 5-mg Revlimid capsules. Additionally, the safety performance of different gloves was tested. RESULTS: A total of 18 samples were analyzed and the results revealed that all samples were contaminated with lenalidomide. Our questionnaire revealed that all pharmacists handled the blister packages with their bare hands when they were checking the remaining capsules of lenalidomide. We analyzed gloves made from four different materials (nitrile, polyvinyl chloride, latex, and polyethylene) and found no permeability in any glove type. CONCLUSION: We conclude that the spent blister package is a potential source of exposure to lenalidomide. All medical staff and caregivers should wear gloves when they handle lenalidomide.

Safety and Effectiveness of Ixazomib Dose-escalating Strategy in Ixazomib-Lenalidomide-Dexamethasone Treatment for Relapsed/Refractory Multiple Myeloma.

BACKGROUND/AIM: Gastrointestinal toxicity is common in patients receiving common therapy of ixazomib with lenalidomide and low-dose dexamethasone (IRd) for relapsed/refractory multiple myeloma. Here, we investigated the safety and effectiveness of ixazomib dosing schedules. PATIENTS AND METHODS: We retrospectively evaluated 17 consecutive patients treated with IRd (10 patients on ixazomib dose-escalation strategy (2.3 mg starting dose); seven patients on standard dose). RESULTS: The incidence of grade 3 or more haematological and grade 2 or more non-haematological adverse events was lower in the dose-escalation group than in the standard-dose group, and only that of diarrhoea was significantly lower. The median time to treatment interruption was significantly longer in the dose-escalation group than in the standard-dose group. There was no significant difference in the overall response rate (20% vs. 43%) and disease control rate (70% vs. 86%). CONCLUSION: A dose-escalation strategy to optimise ixazomib dosing may reduce treatment interruption due to adverse events without compromising its antitumor activity.

[Comparison of Chemical Behavior of Original and Generic Docetaxel Formulations as Non-alcoholic Preparations: Discussion about Diluent Solvents for Docetaxel].

　Although generic anti-tumor agents are in wide clinical use, they have not in all cases been shown to be equivalent to the original agents after preparation. In the present study, original and generic docetaxel formulations were compared with respect to stability when prepared as a non-alcoholic solution for use. When the original formulation was diluted with physiological saline solution to make a non-alcoholic preparation, the concentration decreased with time, whereas no such decrease occurred when a preparation of the generic formulation was made in a similar manner. With both the original and generic formulations, no decrease in docetaxel concentration with time was found after dilution with 5% glucose solution. On the basis of these results, it is concluded that the behaviors of original and generic docetaxel formulations are not equivalent when prepared, but that the original and generic formulations can be taken to be equivalent if they are diluted with 5% glucose solution at preparation.

[Effectiveness of steroids for the rash side effect of pemetrexed].

Rash is a common side effect of pemetrexed(PEM). In clinical trials overseas, patients were prescribed with dexamethasone(DEX), as a prevention against skin rash. Four mg of DEX was orally administered twice daily on the day prior to, day of,and day after the infusion of pemetrexed. The results showed suppression of the incidence and severity of rash. However, the dosage and period of medication was not fully verified. A recent survey was conducted retrospectively, with 81 patients who started PEM monotherapy from May 2009 to August 2010, to study the effectiveness of steroid rash prevention. The patients were classified into the non-administered group(47 patients), who were not given DEX, and the prophylaxis group(34 patients), who were given a median dose of DEX(2mg×3 days). The incidence of rash in the non-administered group was 36.2%, and 23.5% for the prophylaxis group. The severity of rash for the non-administered group was G1: 27.7%, G2: 8.5%; and for the prophylaxis group it was G1: 20.6%, G2: 2.9%. The incidence and severity of rash of the prophylaxis group was statistically and significantly lower than that of the non-administered group. This study shows that a small dosage of steroid is a possible precautionary or preventive measure for rash. Therefore, in order to reduce the incidence and severity of rash, a study with higher doses of medication similar to the clinical trials overseas should be conducted.

Antitumor immune activity by chemokine CX3CL1 in an orthotopic implantation of lung cancer model in vivo.

Due to their chemoattractant properties stimulating the accumulation of infiltrating immune cells in tumors, chemokines are known to have antitumor effects. Fractalkine, a unique CX3C chemokine, is expressed in activated endothelial cells, while its receptor, CX3CR1, is expressed in cytolytic immune cells, such as natural killer cells, monocytes and some CD8+ T cells. The biological properties of cancer cells are affected by the implantation organ and differences in immune systems, requiring cancer implantation in orthotopic organs in an in vivo experiment. To develop new therapy strategies for lung cancer, an animal model reflecting the clinical features of lung cancer was previously established. This study aimed to determine whether CX3CL1-induced biological functions should be used for immune cell-based gene therapy of lung cancer in the orthotopic implantation model. An orthotopic intrapulmonary implantation of CX3CL1-stable expression in mouse lung cancer (LLC-CX3CL1) was performed to analyze growth. Results showed a significant decrease in tumor growth in the lung compared to the control cells (LLC-mock). Furthermore, the antitumor effects of CX3CL1 were derived from natural killer cell activities in the depletion experiment in vivo. Therefore, CX3CL1 has the potential of a useful therapeutic target in lung cancer.

[Safety analysis of eight patients treated with erlotinib after severe gefitinib-induced liver injury].

Gefitinib and erlotinib are commercially available epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) that are widely used for the treatment of non-small-cell lung cancer (NSCLC). Acute severe liver injury, although rare, has been observed in patients receiving these EGFR-TKIs. Some studies have reported that erlotinib treatment does not cause severe liver toxicity in patients with NSCLC who previously presented with severe liver injury during the course of gefitinib treatment. We retrospectively assessed the occurrence of liver toxicity in patients with NSCLC who were receiving erlotinib and had previously presented with severe gefitinib-induced liver injury.Severe liver injury occurred in only 1 of the 8 patients receiving erlotinib treatment. In this case, erlotinib was discontinued because of the onset of grade 3 skin rash and liver injury. After liver function was restored, erlotinib (100 mg) was administered at a lower dose; nonetheless, grade 4 liver injury occurred. Our findings suggest that it is necessary not only to explain the early symptoms of liver toxicity to patients who are receiving erlotinib treatment and have previously experienced gefitinib-induced severe liver injury but also to more closely monitor liver function.

[Revision of the informed consent form for patients based on investigation of adverse events of mFOLFOX6 regimen].

We retrospectively investigated the frequency and severity of adverse events in 124 patients with colorectal cancer who were treated by mFOLFOX6 regimen from August, 2005 to December, 2006. The incidences of grade 3/4 adverse events were; leucopenia 16%, neutropenia 40%, anemia 11%, thrombocytopenia 7%, febrile neutropenia 7%, nausea 3%, vomiting 2%, anorexia 2%, diarrhea 4%, fatigue 7%, and alopecia 0%. The incidences of all grades and grade 3/4 hypersensitivity reaction were 35% and 4%, and the median number of course when it firstly appeared was 6(range, 1-21). The incidences of all grade and grade 3 peripheral sensory neuropathy were 74% and 6%, and the median number of course when it firstly appeared 11(range, 6-16). The incidences of adverse events in this cohort were similar or lower than those reported in Western countries. Our investigation shows that mFOLFOX6 regimen is tolerable in clinical practice in Japan. The informed consent form was revised based on these results. The incidences of adverse events were renewed to provide useful information and improve self-care ability. The symptoms and the time to appearance of the hypersensitivity reaction and peripheral sensory neuropathy were added. We think it is important to provide the information based on the clinical practice.

[Comparative evaluation of adverse reactions between gefitinib and erlotinib treatments in the same patients].

Gefitinib is an orally active, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is widely used in the treatment of advanced non-small-cell lung cancer (NSCLC). Erlotinib, which has the same mechanism of action as gefitinib, has been recently approved in Japan. We retrospectively investigated the adverse reactions in 16 patients who had received erlotinib after failure of gefitinib treatment. We examined the adverse reactions that occurred during gefitinib or erlotinib treatment using an electronic chart system. Anorexia was more frequent with erlotinib than with gefitinib treatment. Further, anorexia and diarrhea were significantly more severe with erlotinib than with gefitinib treatment. Most adverse reactions developed earlier during the course of erlotinib treatment than during the course of gefitinib treatment. In one patient who had received gefitinib treatment without pulmonary toxicity, erlotinib had to be discontinued due to the development of interstitial pneumonia. Our findings suggest that adverse reactions such as anorexia and diarrhea should be carefully monitored soon after starting erlotinib in advanced NSCLC patients in whom gefitinib treatment has been ineffective, because these reactions will occur sooner and would be more severe in erlotinib treatment.

CCL21 promotes the migration and adhesion of highly lymph node metastatic human non-small cell lung cancer Lu-99 in vitro.

To develop new therapy strategies for lung cancer, we established an animal model, which reflects the clinical features of mediastinal lymph node metastasis of lung cancer. This study was designed to determine whether CCL21 induced biological functions associated with the metastasis of highly lymph node metastatic human non-small cell lung cancer (NSCLC) selected by our model. Orthotopic intrapulmonary implantation of human NSCLC (Lu-99 and A549) was performed to analyze the metastatic characteristics of these cells. The expression of CCR7, which is a receptor of CCL21, was detected using CCL19 [also called EBI1-ligand chemokine (ELC)]-Fc chimera by flow cytometric analysis. The effects of CCL21 on the migration, adhesion and growth of human NSCLC were investigated. After orthotopic implantation of human NSCLC cell lines, Lu-99, but not A549, metastasized to mediastinal lymph nodes, forming large size nodules, and expressed CCR7 on the surface. Accordingly, its ligand CCL21 induced chemotactic migration and alpha4beta1-mediated adhesion to VCAM-1 of Lu-99. The expression of CCR7 and vigorous responses to its ligand CCL21 potentially account for lymph node metastasis of a human NSCLC line Lu-99.

Prevention of intrahepatic metastasis by curcumin in an orthotopic implantation model.

Curcumin has been shown to have potent anti-metastatic activity, however, its mechanism of action is still unclear. Here, we analyzed the anti-metastatic mechanism using hepatocellular carcinoma, CBO140C12 cells. Daily oral administration of curcumin suppressed intrahepatic metastasis in a dose-dependent manner, whereas the growth of implanted tumors was not affected. We next examined the effect of curcumin on several metastatic properties in vitro. Curcumin inhibited the invasion of tumor cells through Matrigel-coated filters and the production of MMP-9. In addition, curcumin significantly inhibited adhesion and haptotactic migration to fibronectin and laminin without affecting the expression of integrins on the cell surface. Furthermore, the formation of actin stress fibers was affected by treatment with curcumin. These results suggested that curcumin suppressed the intrahepatic metastasis mediated by the inhibiton of several metastatic properties, in which the functional alteration of cytoskeletal organization, at least in part, could play an important role.

TAC-101 inhibits intrahepatic metastasis of orthotopically implanted murine hepatocellular carcinoma.

The anti-metastatic effect of 4-[3,5-bis(trimethylsilyl)benzamido]benzoic acid (TAC-101) was investigated using our established intrahepatic metastasis model. Orthotopic implantation of a fragment of CBO140C12 hepatoma into the liver resulted in the formation of a solitary tumor nodule and its intrahepatic metastasis. Daily oral administration of TAC-101 at a dose of 8 mg/kg resulted in a significant inhibition of intrahepatic metastasis, but did not affect the growth of the tumor at the implanted site. The down-regulation of transcriptional anti-activator protein-1 (AP-1) activity by TAC-101 paralleled the inhibition of cell invasion and migration through the repression of expression of the mRNAs for urokinase-type plasminogen activator (u-PA) and its receptor (u-PAR). These findings suggest that TAC-101 may improve therapeutic efficacy for liver cancer patients to prevent intrahepatic metastasis.

Increased surgical stress promotes tumor metastasis.

BACKGROUND: Although it is well-known that excessive surgical stress augments the growth of residual cancer and metastasis, whether surgical stress is increased according to the degree of surgical manipulation and can consequently lead to the enhancement of cancer metastasis has not been thoroughly examined. Moreover, the molecules associated with response for stress-enhanced metastasis have not been well-analyzed. The aim of this study was to examine whether cancer metastasis is enhanced with an increase of surgical stress with an experimental lung metastasis model and to analyze the related molecules responsible for stress-enhanced metastasis. METHODS: Colon 26-L5 carcinoma cells (1.5 x 10(4)/mouse) were injected intravenously into 6-week-old female BALB/c mice (Japan SLC, Hamamatsu, Japan). Two hours later, the mice were divided into 5 groups: untreated controls (the C group); mice given anesthesia only (the A group); mice given anesthesia and laparotomy (the AL group); mice given anesthesia, laparotomy, and appendectomy (the ALAp group); and mice given anesthesia, laparotomy, appendectomy, and left hepatic lobectomy (the ALApH group). The anesthesia procedures were the same in all groups (intraperitoneal administration of 0.8 mg/mouse sodium pentobarbital). In the AL, ALAp, and ALApH groups, a 3-cm long laparotomy was performed, and the time of the whole operation was just 5 minutes. All mice were killed 14 days after the procedures, and the number of lung metastases on the lung surface was counted manually. At the same time, BALB/c mice without tumor burden were given the same 5 kinds of surgical stress, and the messenger RNA expression of various metastasis-related molecules in the lung was measured with reverse transcriptase-polymerase chain reaction at 6, 24, and 48 hours after surgical stress. We also examined the effect of ONO-4817 (an inhibitor of matrix metalloproteinases ([MPs]) on lung metastasis in the mice with the 5 kinds of surgical stress. RESULTS: The numbers of lung metastases on the lung surface and the messenger RNA expression of MMP-9, membrane type IBMMP, and urokinase-type plasminogen activator at 24 hours after surgery were enhanced in proportion to the degree of surgical stress. Moreover, ONO-4817 significantly inhibited lung metastasis. CONCLUSION: These results strongly suggest that increased surgical stress augments cancer metastasis via surgical stress-induced expression of proteinases in the target organ of metastasis.