Mamiko Tsugane

Can Anti-Infective Drugs Improve the Infection-Related Symptoms of Patients with Cancer during the Terminal Stages of Their Lives?

BACKGROUND Appropriate use of anti-infective drugs is essential in clinical practice. No evidence-based guidelines or protocols have been published on the appropriate use of anti-infective drugs in patients receiving palliative care as yet. METHODS The medical records, which included the demographic data of patients, anti-infective drug use, bacteriologic findings, symptoms, and hematologic findings were reviewed retrospectively to determine the potential factors that contribute to symptom improvement of patients in terminal phase. RESULTS Seventy-one patients (64%) who received anti-infective drugs and had a total of 326 episodes of infection were assessed. Symptom improvement was seen in 33.1%. A total of 22.6% of episodes were started on anti-infective drugs during the last week of life and the symptom improvement in these episodes was 9.2%. Symptom improvement was hardly observed when the anti-infective drug was administered during the last week of life. The association between the decrease in the C-reactive protein (CRP) levels, the decrease of the leukocyte count, reduction of fever, and symptom improvement was determined. The decrease of CRP levels was 42.4%; leukocyte, 56.7%; and reduction of fever was 28.4%. The symptom improvement of individual treatment history was also investigated. The symptom improvement of the group who took positive treatment such as chemotherapy, radiotherapy, surgery, and catheter placement was significantly lower than that of no-treatment group. CONCLUSIONS Active cancer treatment probably induces the symptoms related to infection and the use of anti-infective drugs. Unnecessary and excessive treatment should be avoided, and the symptoms should be managed with consideration of the patients state of mind in order to improve the quality of life of terminally ill patients.

Can Gradual Dose Titration of Ketamine for Management of Neuropathic Pain Prevent Psychotomimetic Effects in Patients With Advanced Cancer

Background: Ketamine is often used to manage neuropathic pain in patients with cancer. However, it occasionally causes psychotomimetic effects such as vivid dreams, nightmares, illusions, hallucinations, and altered body image. Objective: To examine whether gradual dose titration of ketamine for management of neuropathic pain prevents psychotomimetic effects in patients with advanced cancer. Methods: This was a retrospective chart review. We administered ketamine when neuropathic pain in patients with advanced cancer became refractory to opioids and oral adjuvant analgesics. The starting dose of ketamine was 10 mg/d by continuous intravenous infusion. The dose was gradually increased by 10 mg/d every 4 to 6 hours to 50 mg/d or until the pain was relieved. It was subsequently increased by 25 mg/d every 12 to 24 hours until the pain was relieved. Results: For this study, we enrolled 46 patients with advanced cancer. The mean age was 52.2 ± 16.9 years. The mean dose at onset of action and maximum dose of ketamine were 56 ± 58 and 272 ± 214 mg/d, respectively. The mean pain intensity (numerical rating scale) decreased significantly from 7.3 ± 2.0 to 3.5 ± 2.2 after the administration of ketamine (P < .01). The effectiveness was 69.5%. No psychotomimetic effect of less than 300 mg/d was observed during the introduction phase even though psychotropic drugs were not prescribed. Mild sedation was observed in 3 patients (7%) as the only adverse effect during the introduction phase. Conclusion: Gradual dose titration of ketamine for management of neuropathic pain can prevent psychotomimetic effects in patients with advanced cancer.

A Retrospective Chart Review of Terminal Patients with Cancer with Agitation and Their Risk Factors

BACKGROUND Agitated delirium is often observed in terminal patients with cancer. To clarify the risk factors for agitated delirium in terminal patients with cancer, we conducted a retrospective chart review of 126 patients with cancer who died at a university hospital in 2008. METHOD As a working definition, we define agitated delirium as a score of 2 or more in item 9 of the Memorial Delirium Assessment Scale with diurnal variation. RESULTS The results were as follows: agitated delirium was observed in 49 (42%) of the 115 patients, and it occurred within the last week before death in 49% of the patients. Univariate analysis revealed older age, male gender, smoking history, lung cancer, diabetes, and high C-reactive protein (CRP) value as major risk factors, while dendritic analysis revealed lung cancer, high CRP value, diabetes, older age, and smoking history as key factors for predicting agitation. CONCLUSION It is necessary to consider risk factors in order to categorize terminal patients with cancer into high- and low-risk groups and undertake possible counter-measures.

Can milnacipran used for neuropathic pain in patients with advanced cancer cause neuromuscular and somatosensory disorders

BACKGROUND Milnacipran is one of the classes of drugs that are serotonin and norepinephrine reuptake inhibitors (SNRIs). It is a promising drug for the treatment of neuropathic pain in patients with advanced cancer. However, we found that neuromuscular and somatosensory disorders occurred when milnacipran was used as an adjuvant analgesic. CASE REPORT A 66-year-old woman with a history of neuropathic pain was given 15 mg of milnacipran after dinner. The next morning she developed stiffness of the fingers, numbness in the mandible, and the soles of her feet felt swollen. Milnacipran was discontinued and her symptoms disappeared immediately. We managed this case, which was becoming severe, by discontinuing milnacipran on early detection of symptoms. DISCUSSION This is the first report that demonstrates an adverse reaction of milnacipran when used as an analgesic adjuvant, and not as an antidepressant drug, for neuropathic pain in patients with advanced cancer. The analgesic effect of SNRIs will likely be used in the management of neuropathic pain in the future; however, clinicians should be aware of the early adverse reactions to these agents.

A microwell device for measurement of membrane transport of adherent cells

We developed the microwell device for measurement of membrane transport of single adherent cells. As the cells in a population (e.g., tumor) is inevitably heterogeneous, a technique to measure the transport activities at a single-cell level is needed. When adherent cells were cultured on the microwells with ~10 μm diameter, they spread over the opening to form the closed picoliter space. Thus, molecules exported from cells accumulate in such a space and be detected by fluorescence imaging. In this report, we show that, by employing horizontal microwell design, materials exported from the cell membrane can be visualized without overlapping with the cell, increasing the S/N ratio of the fluorescence signal. Efflux of the cancer drug transported by the multidrug resistance protein was detected.

Reverse Transcription Polymerase Chain Reaction in Giant Unilamellar Vesicles

We assessed the applicability of giant unilamellar vesicles (GUVs) for RNA detection using in vesicle reverse transcription polymerase chain reaction (RT-PCR). We prepared GUVs that encapsulated one-pot RT-PCR reaction mixture including template RNA, primers, and Taqman probe, using water-in-oil emulsion transfer method. After thermal cycling, we analysed the GUVs that exhibited intense fluorescence signals, which represented the cDNA amplification. The detailed analysis of flow cytometry data demonstrated that rRNA and mRNA in the total RNA can be amplified from 10–100 copies in the GUVs with 5–10 μm diameter, although the fraction of reactable GUV was approximately 60% at most. Moreover, we report that the target RNA, which was directly transferred into the GUV reactors via membrane fusion, can be amplified and detected using in vesicle RT-PCR. These results suggest that the GUVs can be used as biomimetic reactors capable of performing PCR and RT-PCR, which are important in analytical and diagnostic applications with additional functions.

Microchamber Device for Detection of Transporter Activity of Adherent Cells

We present a method to detect the transporter activity of intact adherent cells using a microchamber device. When adherent cells are seeded onto the poly-di-methyl siloxane substrate having microchambers with openings smaller than the size of a cell, the cells form a confluent layer that covers the microchambers, creating minute, confined spaces. As substances exported across the cell membrane accumulate, transporter activity can be detected by observing the fluorescence intensity increase in the microchamber. We tested the microchamber device with HeLa cells over-expressing MDR1, an ATP-binding cassette transporter, and succeeded in detecting the transport of fluorescence-conjugated paclitaxel, the anti-cancer drug, at the single-cell level.