Effects of Chemotherapy-Induced Neutropenia on Overall Survival in Patients With Unresectable or Metastatic Urothelial Carcinoma to Gemcitabine Plus Cisplatin Combination Chemotherapy.

BACKGROUND: Chemotherapy-induced neutropenia (CIN) is an important dose-limiting toxicity of chemotherapy. However, evidence suggests that the occurrence of CIN may be predictive of treatment outcome. Indeed, studies have revealed that the onset of CIN is associated with a good chemotherapeutic response. OBJECTIVE: The purpose of this study was to investigate the association between the onset of CIN and overall survival in patients with unresectable or metastatic urothelial carcinoma (UC) who received a combination regimen of gemcitabine and cisplatin (GC). METHODS: Medical records from 56 patients with unresectable or metastatic UC who were treated with a combination GC regimen between December 2005 and May 2016 were retrospectively analyzed to investigate the association between CIN development and survival. RESULTS: The median duration of survival was 521 days (95% CI = 147-193 days) for patients with severe CIN and 287 days for patients without CIN. Additional multivariate analysis revealed that both the presence of severe CIN (hazard ratio [HR] = 0.399; 95% CI = 0.180-0.880, P = 0.023) and baseline hemoglobin (HR = 2.167; 95% CI = 1.170-4.014, P = 0.014) represented independent prognostic factors for the survival of patients with unresectable or metastatic UC receiving GC treatment. Conclusion and Relevance: CIN onset was associated with longer survival in patients receiving GC therapy for unresectable or metastatic UC, suggesting that neutropenia monitoring during GC chemotherapy may be predictive of treatment efficacy.

[The 10th Annual Meeting of the Japanese Society for Pharmaceutical Palliative Care and Sciences].

　The 10th Annual Meeting of the Japanese Society for Pharmaceutical Palliative Care and Sciences was held at Act City Hamamatsu, Japan, with a total of 2634 participants in attendance. The theme of the meeting was realized through a number of new concepts, such as a debate symposium, information sessions, nurses' workshops, and so on. The results obtained from the participation questionnaire (n=438), which were aggregated up to 1 month following the end of this year's meeting, revealed that 89% of the participants at considered it to have been appealing. In particular, 63% of the participants favored the adoption of a debate symposium whereby it was possible to ask and respond to questions in real time. In the free comments section of the questionnaire, the participants expressed how they felt the debate symposium made it easy to give their opinions, and that this element might be further developed in the future. They also stated that they found the introduction of the Clica system effective in terms of making the annual meeting an active learning place. One issue that was highlighted concerned the observation that the hall used to host the symposium was designed as a concert venue, which meant it was highly shielded from the outside environment, in addition to access to the internet being blocked. I hope that many of the projects from this Annual Meeting will serve to guide the future style of the Society's Annual Meetings.

Drug-related genetic polymorphisms affecting severe chemotherapy-induced neutropenia in breast cancer patients: A hospital-based observational study.

Chemotherapy-induced neutropenia (CIN) is one of the major adverse events that necessitate chemotherapy dose reduction. This study aimed to evaluate the association between grade 4 neutropenia and genetic polymorphisms in breast cancer patients. In this genetic polymorphism association study, peripheral blood samples from 100 consecutive breast cancer outpatients, between August 2012 and September 2014, treated with doxorubicin and cyclophosphamide (AC) combination chemotherapy were genotyped for polymorphisms in adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1), cytochrome P450 (CYP) enzyme-coding genes (CYP2B6 and CYP3A5), glutathione S-transferase (GST), and excision repair cross-complementing 1 (ERCC1). Associations between grade 4 neutropenia and genotypes as well as risk factors were examined using multivariate logistic regression. From 100 patients, 32.0% had grade 4 neutropenia. Multivariate logistic regression analysis revealed that ERCC1 118C > T (odds ratio [OR], 3.43; 95% confidence interval [CI], 1.22-9.69; P = 0.020), CYP2B6*6 (OR, 4.51; 95% CI, 1.21-16.95; P = 0.025), body mass index (BMI) (OR, 6.94; 95% CI, 1.15-41.67; P = 0.035), and baseline white blood cell (WBC) count (OR, 2.99; 95% CI, 1.06-8.40; P = 0.038) were significant predictors of grade 4 neutropenia. ERCC1 and CYP2B6 gene polymorphisms were associated with the extent of grade 4 neutropenia in patients receiving AC chemotherapy. In addition to previously known risk factors, BMI and WBC counts, ERCC1 and CYP2B6 gene polymorphisms were also identified as independent strong predictors of grade 4 neutropenia.

Relationship between ABCB1 gene polymorphisms and severe neutropenia in patients with breast cancer treated with doxorubicin/cyclophosphamide chemotherapy.

Chemotherapy-induced neutropenia is one of the major adverse events which results in the reduction of chemotherapy. Doxorubicin is a substrate of the adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) transporter; reportedly, ABCB1 polymorphisms influence doxorubicin pharmacokinetics. We evaluated the association between chemotherapy-induced neutropenia and ABCB1 polymorphisms in patients with breast cancer. We investigated 141 patients with breast cancer treated with doxorubicin and cyclophosphamide (AC) chemotherapy. Peripheral blood samples obtained from patients were genotyped for the ABCB1 2677G>T/A and 3435C>T polymorphisms. The genotypes were then investigated for their association with grade 3 or greater neutropenia, and further their risk factors were examined using a multivariate logistic regression. The proportion of patients with grade 3 or greater neutropenia was 85.7% in the homozygous variant group, and 80% and 58.6% in the heterozygous variant and GG genotype groups, respectively (p = 0.021). The multivariate logistic regression analysis revealed that the ABCB1 2677G>T/A polymorphism was a strong predictor of grade 3 or greater neutropenia (odds ratio: 3.76; 95% confidence interval: 1.44-9.81; p = 0.007). ABCB1 polymorphisms may influence the extent of chemotherapy-induced neutropenia in AC combination-treated patients with breast cancer.

[Analysis of risk factors of drug-induced lung injury in patients receiving gemcitabine treatment].

Gemcitabine hydrochloride is a very safe medicine that even outpatients can be administered, and the bone marrow depression that is the dose limiting factor remains moderate and does not need special treatment, although it is confirmed in most cases. Meanwhile, caution is required because there is a possibility of drug-induced lung injury and death due to high frequency, compared with the appearance rate described in the packaging insertion. We investigated the clinical background of a patient in whom drug-induced lung injury appeared, and clarified the risk factor by administering gemcitabine hydrochloride. Males, people aged 65 or over, those with a smoking history and those undergoing first-line chemotherapy treatment are at risk of drug-induced lung injury. Attention must be paid to the occurrence of drug-induced lung injury, to examining the clinical course, the chest image, and the blood test, and to do earlier detection, the offending medicine discontinuance, and beginning of the treatment.

Role of the community pharmacy in palliative care: a nationwide survey in Japan.

PURPOSE: The role of the community pharmacy in palliative care may become increasingly important in Japan. There has been however no investigation to date of community pharmacies in Japan that takes into account their role in enabling palliative care in the home. The aims of the present study were thus to evaluate (1) the availability of narcotics through community pharmacies and the experience of pharmacists in prescribing narcotics; (2) availability of patient counseling provided by pharmacists; (3) pharmacist-perceived difficulties in treating cancer patients with narcotics; and (4) useful strategies to make narcotics more easily available to patients. METHODS: We sent 3000 questionnaires to community pharmacies as a representative national sample, and 1036 responses were analyzed (response rate: 34.5%). RESULTS: We found that 77% of community pharmacies had a narcotics retailer license, and that approximately 50% received prescriptions for and prepared narcotics each month. Approximately 70% of community pharmacies received however only 3 narcotics prescriptions each month. Half of the pharmacists reported that they did not counsel patients, primarily because they lacked information about the patient. The most common area reported by pharmacists as being extremely difficult was communicating with terminally ill cancer patients. To make narcotics more easily available to patients, 76% of community pharmacists felt it was important to be able to return narcotics to wholesalers. CONCLUSION: The present study suggests that there are many problems in community pharmacy that need to be addressed to improve access to palliative care in the home, including (1) increased sharing of patient information; (2) increasing community pharmacists' communication skills; and (3) changing current regulations regarding the distribution of narcotics. If these issues are addressed, palliative care in the home could become more widely accepted.

Suppression of dopamine-related side effects of morphine by aripiprazole, a dopamine system stabilizer.

Dopamine receptor antagonists are commonly used to counter the adverse effects of opioids such as hallucinations, delusions and emesis. However, most of these agents themselves have side effects, including extrapyramidal symptoms. Here, we investigated the effect of the dopamine system stabilizer aripiprazole on morphine-induced dopamine-related actions in mice. Morphine-induced hyperlocomotion and reward were significantly suppressed by either the dopamine receptor antagonist prochlorperazine or aripiprazole. Catalepsy was observed with a high dose of prochlorperazine, but not with an even higher dose of aripiprazole. The increased level of dialysate dopamine in the nucleus accumbens stimulated by morphine was significantly decreased by pretreatment with aripiprazole. These results suggest that the co-administration of aripiprazole may be useful for reducing the severity of morphine-induced dopamine-related side effects.

[Survey on patients' satisfaction with opioid rescue guidance by pharmacists].

To examine the influence of drug therapy guidance by pharmacists on the use of a rescue dose (RD) for opioid analgesics (opioids) and pain as well as drug therapy guidance in cancer pain treatment, we conducted a patient satisfaction survey. The subjects were 56 cancer patients undergoing opioid therapy in hospitals belonging to the Symptom Control Research Group (SCORE-G). The survey period was 2 months (from November 1 until December 31, 2006). Drug therapy guidance regarding the use of RD was performed twice in each patient to evaluate the patients' satisfaction. RD was prescribed in 87.8% of the patients in the first guidance and in 80.5% in the second guidance periods. The proportion of patients who used RD significantly increased from 63.8% to 87.5%. Five items significantly improved in the second guidance period: "marked analgesic effects," "satisfaction with current treatment," "correct understanding of RD usage," "relief through RD," and "appropriate use of RD." On comprehensive evaluation following the second round of guidance, 81% of the patients reported overall satisfaction, and 78% reported the usefulness of guidance in pain treatment. These results suggest that positive guidance by pharmacists increases patients' satisfaction. In providing guidance, it was important to confirm the characteristics and side effects of opioids as well as the necessity of RD to patients accurately and repeatedly.

[Cost-effectiveness analysis of 5-HT3 receptor antagonist drugs in cancer chemotherapy].

Recently, ambulatory treatment centers (ATC) are markedly increasingboth in number and scale. It is therefore important to consolidate an efficient therapeutic system. A decrease in both treatment time and waitingtime leads to not only the improvement of the quality of life (QOL) for patients but also the efficient use of personnel and running costs for medical institutions by reducingthe bed occupation rate. In ATC, 5-HT3 receptor antagonists are extensively used for high emetic risk patients. However, their high cost and prolonged treatment causes one of the problems in improvingthe efficiency of the therapeutic system when they are administered by intravenous infusion. Amongthe 4 types of 5-HT3 receptor antagonists (injections) currently available in Japan, azasetron is the only drugthat is not designated as a powerful drug and that can be administered by bolus intravenous infusion. In this study, we investigated azasetron and granisetron from the standpoint of pharmacoeconomics with a simulation model using the results of clinical studies in Japan. Accordingto the results of cost-effectiveness analysis, therapeutic and time costs per patient for azasetron 10 mgand granisetron 2 mg (calculated in consideration of both medical institutions and patients) was 8,219 and 10,193 yen, respectively. This gap was attributable to the time loss due to the difference in administration methods. The result suggests that this time loss is more significant not only for patients but also for medical staff than the loss attributable to the drugcost. Furthermore, the bolus intravenous infusion of azasetron is considered superior to the non-bolus intravenous infusion of granisetron from a pharmacoeconomic standpoint. It is desirable to choose the appropriate administration method of 5-HT3 receptor antagonists in various chemotherapy regimens for the purpose of reducingthe treatment time and promotingthe efficiency of the therapeutic system at ATCs.

[Effects of fasudil on neuropathic pain-like state in mice].

The aim of the present study was to investigate the role of protein kinases within the spinal cord in the development of a neuropathic pain-like state induced by partial sciatic nerve ligation in mice. Thermal hyperalgesia induced by nerve ligation in mice was markedly suppressed by either repeated intrathecal (i.t.) pre-treatment or post-treatment with the selective protein kinase (PKC) inhibitor RO-32-0432 and the selective Rho kinase inhibitor Y-27632. In contrast, sciatic nerve ligation-induced thermal hyperalgesia was not observed by repeated i.t. pre-treatment with the selective PKA inhibitor KT5720. Interestingly, thermal hyperalgesia induced by nerve ligation in mice was significantly suppressed by repeated i.t. post-treatment with fasudil, which possesses the inhibitory effect of several protein kinases including PKC and Rho kinase. Collectively, these findings suggest that a long-lasting activation of PKC and RhoA/Rho kinase pathways in the spinal cord may be responsible for the development of thermal hyperalgesia induced by nerve ligation in mice. The present data raise the fascinating possibility that i.t. or epidural administration with fasudil may be useful for the treatment of neuropathic pain.

Usefulness of the dopamine system-stabilizer aripiprazole for reducing morphine-induced emesis.

In the management of pain, nausea and vomiting are some of the most distressing adverse effects induced by opioids. In the present study, we investigated the effect of the dopamine system-stabilizer aripiprazole on morphine-induced emesis. Morphine induced retching and vomiting in a dose-dependent manner in ferrets. The emetic effect of morphine was significantly suppressed by pretreatment with either the dopamine receptor antagonist haloperidol or aripiprazole. These results suggest that the co-administration of aripiprazole may be useful for reducing the severity of morphine-induced emesis.