Frequency of Myoclonus and its Countermeasures in Terminally Ill Patients with Cancer: A Single-Center Retrospective Study.

Myoclonus is a relatively rare involuntary movement that is often observed in palliative care settings and that can cause patient distress. The purpose of this study is to investigate the occurrence of myoclonus and countermeasures against it in terminally ill patients with cancer diagnosed by palliative care specialists at Komaki City Hospital, Japan. We retrospectively reviewed patients with terminal cancer who received palliative care consultations between January 2018 and May 2019 and who were diagnosed with myoclonus by palliative care specialists, using electronic medical records. Patient demographics, time from onset of myoclonus to death, daily opioid use, countermeasures, and outcome of myoclonus were assessed. Of 360 patients examined during this period, 45 (12.5%) were diagnosed with myoclonus. Median age was 71 (range, 43-88) years; median time from onset of myoclonus to death was 8 days (range, 0-56); opioid usage was present in 39 patients (morphine, oxycodone, and fentanyl: n = 6, 21, and 12, respectively); and median oral morphine equivalent at onset of myoclonus was 60 mg (range, 12-336 mg). Myoclonus treatment was administered to 21 patients (opioid dose reduction, opioid switching, and others: n = 14, 3, and 4, respectively). Myoclonus is a common complication in patients with terminal cancer.

[Xanthan Gum-based Food Thickeners Reduce Disintegration Time of Medical and OTC Loxoprofen Sodium Tablets].

Xanthan gum-based food thickeners have been reported to potentially interfere with tablet disintegration. Loxoprofen sodium (LOX) is widely used as an antipyretic analgesic and is expected to provide rapid pain relief. In this study, we aimed to investigate the impact of a xanthan gum-based food thickener on LOX tablet disintegration. We used four different brands each of medical and OTC-LOX tablets, each containing 60 mg of LOX as the sole active ingredient. Depending on the brand, tablet hardness varied between 50.1-96.6 N and was not associated with the disintegration time. Disintegration times for medical tablets not immersed in the food thickener were 536±215, 621±159, 348±22, 369±42 s and for OTC tablets, were 358±20, 336±13, 292±13, 172±27 s. Immersion in the food thickener for 15 min reduced medical tablet disintegration time to 177±46 and 233±150 s (the third and fourth brands were disintegrated during immersion), and that for OTC tablets to 77±40, 75±110, and 37±85 s (the fourth brand was disintegrated during immersion). Despite each tablet containing different pharmaceutical additives, no correlation was found between disintegration time and presence of superdisintegrants. The OTC tablet with a light anhydrous silicic acid coating exhibited the shortest disintegration time. Thus, the disintegration time of LOX tablets is accelerated when immersed in the xanthan gum-based food thickener, potentially leading to rapid pain relief for patients.

Differences in serum selenoprotein P profile between C57BL/6 and BALB/c mice fed high-fat diet.

BACKGROUND: C57BL/6 mice generally show hyperglycaemia and insulin resistance when fed a high-fat diet (HFD) compared to those of BALB/c mice. However, whether these strains also show different expression profiles of selenoprotein P, a diabetes-related hepatokine, after HFD feeding is unclear. We investigated the effects of HFD on body weight, glucose metabolism, and plasma selenoprotein P levels in C57BL/6 and BALB/c mice. METHODS: Male C57BL/6 and BALB/c mice aged seven weeks were divided into normal diet (ND) and HFD groups. Fasting body weights and blood sugar levels were measured weekly. Blood specimens were collected after 16 h of fasting (in weeks 7, 9, and 11) and after 24 h of subsequent refeeding (in weeks 9 and 11) to analyse plasma selenoprotein P and insulin levels. RESULTS: The mean body weight of the HFD group was consistently higher than that of the ND group for both strains. However, a significant elevation in fasting plasma glucose levels from the early stage was observed only in the HFD group of C57BL/6 mice. In BALB/c mice, a difference in fasting glucose levels between the HFD and ND groups was observed after nine weeks. After seven, nine, and eleven weeks, the fasting plasma insulin levels were higher in the HFD group than in the ND group for both strains. During this period, plasma selenoprotein P levels in the HFD group were significantly higher than those in the ND group of C57BL/6 mice. However, BALB/c mice did not show a significant difference in plasma levels of selenoprotein P between the ND and HFD groups. After refeeding, the plasma insulin and selenoprotein P levels increased compared to those observed during fasting in the ND group for both strains. Elevation of insulin levels, but not of selenoprotein P levels, after refeeding was noticed in the HFD group for both strains. Plasma selenoprotein P level after refeeding was significantly lower than that during fasting in the HFD group of C57BL/6 mice. CONCLUSION: Unlike C57BL/6 mice, BALB/c mice did not show elevated fasting plasma selenoprotein P levels despite HFD feeding. Additionally, the pattern of selenoprotein P levels in the plasma after refeeding differed between C57BL/6 and BALB/c mice. These differences in selenoprotein P expression among strains may be related to different susceptibilities of individuals to diabetes.

Early Palliative Care Improves Overall Survival in Patients With Lymphoma: A Single-institution Retrospective Study.

BACKGROUND/AIM: Early palliative care (EPC) intervention in patients with solid tumors can provide many benefits. However, studies on patients with hematological malignancies are limited, and there is no data on patients with lymphoma. We conducted a preliminary retrospective survey of palliative care (PC) intervention in patients with lymphoma to clarify the effect of EPC on overall survival (OS). PATIENTS AND METHODS: The first palliative care consultation (PC1) was retrospectively reviewed from medical records in Japan. Patients with lymphoma requiring inpatient PC at our institution from January 2012 to December 2018 were recruited. We conducted receiver operating characteristic (ROC) analysis; patients were divided into two groups (early and delayed), and the survival periods and palliative care team (PCT) referral details were compared. RESULTS: The analysis included 77 patients with lymphoma [median age, 71 (64-79)] years. The median period to PC1 from the initial diagnosis was 395 (180-1,086) days. ROC analysis revealed an optimal PC intervention timing of 140 days. OS was significantly longer in the early group than that in the delayed group. The most common counseling details for the PCT were symptom relief and palliative care transfer (36.8% and 35.2%, respectively). CONCLUSION: This real-world evaluation of PC intervention for inpatients with lymphoma revealed that PC intervention was provided at approximately 13 months following initial diagnosis. EPC intervention from diagnosis to 140 days may improve OS in patients with lymphoma; however further large-scale studies are required to verify this finding.

Nanointerfacial Layer Effect on Dielectric and Piezoelectric Responses in Chemical Solution-Derived Lead-Free Alkaline Niobate-Based Thin Films.

Since nonpiezoelectric interfacial layers even at the nanoscale significantly affect the performance of lead-free piezoelectric thin films, the quantitative characterization of property changes of thin films due to interfacial layers is of great importance and should be precisely undertaken for piezoelectric microelectromechanical system (MEMS) and nanoelectromechanical system (NEMS) devices. In contrast to widely accepted concepts for interfacial layer thickness estimation based on the existing series capacitor model, we find that the interfacial layer thickness at the top and the bottom interfaces is clearly different in chemical solution deposition (CSD)-derived (K0.5,Na0.5)(Mn0.005,Nb0.995)O3 (KNMN) thin films. Interestingly, the thickness of the bottom interface increases linearly with increasing thin-film thickness, while the thickness of the top interface is constant regardless of the thin-film thickness. In this work, nanointerfacial layer effects of CSD-derived KNMN thin films are theoretically and experimentally addressed in a combinatorial way using a modified series capacitor model. The obtained information is used to envisage the origins and the mechanisms of nonpiezoelectric interfacial layers and associated dielectric and ferroelectric properties of KNMN thin films. Our research connects macroscopic properties with microscopic origins and is greatly facilitated by separating intrinsic and extrinsic contributions to phenomenological behaviors, as well as engineering interface-related properties of the films. We believe these studies to be crucial for the further development and applications of KNN-based lead-free piezoelectric devices, which also open the door to future studies on other lead-free piezoelectric material systems for practical MEMS and NEMS applications.

Multiday corticosteroids in cancer chemotherapy delay the diagnosis of and antimicrobial administration for febrile neutropenia: a double-center retrospective study.

BACKGROUND: Medical staff should promptly administer antimicrobials to patients with febrile neutropenia (FN) to decrease the mortality related to cancer chemotherapy. Corticosteroids, which are used in cancer chemotherapy, have a fever-suppressive effect. This effect could lead to a blunt fever response and any local signs of infection, especially in patients receiving multiday corticosteroid administration. The aim of this study was to determine whether multiday corticosteroid administration in cancer chemotherapy delays the diagnosis of and antimicrobial treatment for FN. METHODS: We conducted a double-center retrospective study in Japanese patients with FN. The patients were divided into two groups based on the corticosteroid administration method, i.e., whether administration was multiday or not. To evaluate the degree of masking on FN by corticosteroids, we assessed the correlation between body temperature variation and time of antimicrobial administration after the initiation of chemotherapy. Risk factors for delayed antimicrobial administration were identified by multiple logistic regression analysis. RESULTS: Two hundred thirteen patients were analyzed. The median time required to body temperature reaching 37.5 °C and for antimicrobial administration was longer in the multiday group than in the non-multiday group, with 0.64 and 0.60 days (P = 0.002 and P < 0.001), respectively. Multiday corticosteroid use was identified as an independent risk factor for delayed antimicrobial administration (odds ratio = 3.94; 95% confidence interval = 1.80-8.62; P < 0.001). CONCLUSIONS: Multiday corticosteroid administration in cancer chemotherapy delayed the diagnosis of and antimicrobial administration for FN. Furthermore, it was the only risk factor for delayed antimicrobial administration. We could thus provide evidence that the diagnosis of and antimicrobial administration for FN in patients receiving multiday corticosteroid administration should not be based on body temperature variation alone.

[Examination of the cause of changing solution color by mixing aminophylline and dopamine, the compatibility of which was indicated by the supplier].

A case in which aminophylline solution was administered to a patient with congestive heart failure is reported and the problems caused by administration were solved by subsequent experiments. Dopamine solution was added from the side route using a mechanical pump, and mixed with aminophylline solution in the main route. Furosemide was administered after clamping and flushing the main route according to the supplier's information that indicated the compatibility of dopamine and aminophylline. However, the aminophylline solution turned black in color 3 h after furosemide administration. Several examinations were carried out to clarify the cause of the incompatibility in this case. The results showed that solutions with all possible combinations, including aminophylline and dopamine, turned black at 24 h after mixing, and the UV absorption at 430 nm increased from 0 to 0.28. UV absorption of the mixed solution increased in a dopamine dose-dependent manner in the range of 1.5-12 mg. When aminophylline was added to physiological saline or hypotonic electrolyte solution, the pH of each solution increased. These results suggested that degradation of dopamine to a melanin-like polymer under alkaline conditions caused the change in color of the solution. It is presumed that dopamine was inappropriately injected into aminophylline solution as the route was clamped tightly to shut out furosemide contamination. Aminophylline and dopamine are often co-administered to patients in critical condition. Thus, even if compatibility of aminophylline with dopamine is indicated by the supplier, they should be administered through separate routes.

Potentiation of the antitumor effect of calcium phosphate cement containing anticancer drug and caffeine on rat osteosarcoma.

BACKGROUND: Several reports suggest diffusion of anticancer agents from bone cement may suppress tumor growth. New drug delivery systems have been developed that incorporate anticancer drugs into calcium phosphate cement (CPC) to maintain high concentrations of anticancer drugs at local sites. We investigated whether CPC implants containing anticancer drugs and caffeine, which enhance the cytocidal effect of anticancer drugs, would enhance their antitumor effects on rat osteosarcomas (SOSN2 cells). METHODS: We calculated the release of cisplatin (CDDP) and caffeine from the CPC and bone cement. The following CPCs were prepared: CPC-only, CPC containing caffeine, CPC containing cisplatin, and CPC containing cisplatin and caffeine. We performed cell growth inhibition assays on SOSN2 cells using culture media previously used to incubate each CPC. We transplanted SOSN2 cells into the tibias of rats, excised the tumor 3 days after transplantation, implanted each CPC and observed subsequent tumor growth. RESULTS: The in vitro sustained-release test demonstrated greater amounts and more persistent release of CDDP and caffeine from CPC than from bone cement and also showed CPC could release the majority of its loaded CDDP and caffeine. Culture media containing CDDP and caffeine inhibited in vitro proliferation of SOSN2 cells, and this inhibitory effect was greater than the inhibition resulting from CDDP alone. Experiments with an in vivo rat model demonstrated greater tumor growth inhibition with CPC containing CDDP and caffeine than with CPC containing CDDP alone. CONCLUSIONS: The study results suggest CPC containing CDDP and caffeine potentiate antitumor effects and may be effective as a local chemotherapeutic method of treating malignant bone tumors.

Impact of serum caffeine monitoring on adverse effects and chemotherapeutic responses to caffeine-potentiated chemotherapy for osteosarcoma.

BACKGROUND: Caffeine can safely enhance the cytocidal effects of anticancer drugs through its DNA repair-inhibiting effect. We have demonstrated in several studies that caffeine-potentiated chemotherapy induces a high complete response rate in patients with osteosarcoma. The present study focused on monitoring and adjusting serum caffeine levels during caffeine-potentiated chemotherapy to reduce adverse effects. METHODS: We utilized a method for rapidly determining caffeine concentration by high-performance liquid chromatography. The maximum caffeine concentration was predicted from the measured concentrations at 24 and 48 h after the beginning of caffeine administration. The caffeine infusion rate was then modified accordingly to prevent the expected final concentration from exceeding 80 microg/ml. The study involved 22 American Joint Committee on Cancer (AJCC) stage IIB high-grade osteosarcoma patients treated with caffeine-potentiated chemotherapy. Nine patients underwent monitoring of their serum caffeine levels (monitoring group), and the remaining 13 patients were not monitored (nonmonitoring group). Toxicities were graded according to the Japan Clinical Oncology Group Toxicity Criteria. RESULTS: Hematological toxic events were well tolerated in both groups. Grade 4 leukocyte toxicity events occurred in both groups. In the nonmonitoring group grade 2 or higher toxicities included 5 elevated aspartate aminotransferase/alanine aminotransferase level events and 17 hyponatremia events versus 1 hyponatremia event in the monitoring group. Histological examination of excised tumor samples after preoperative chemotherapy revealed that chemotherapeutic efficacy in the monitoring group was as good as in the nonmonitoring group. The median follow-up period in all patients was 72 months. Event-free survival was 76%, and overall survival was 100%. CONCLUSIONS: Monitoring and adjusting caffeine levels were achieved without apparent loss of chemotherapeutic efficacy.

The antitumor effect of liposome-encapsulated cisplatin on rat osteosarcoma and its enhancement by caffeine.

BACKGROUND: Drug delivery systems are for the purpose of targeting a drug to a specific tissue selectively and at the same time preventing a drug from accumulating in healthy organs. Liposomes have been proposed as useful drug carriers in targeted drug delivery system and are under investigation in several therapeutic fields. Caffeine has been identified as belonging to the group of xanthines that enhances the action of cisplatin. MATERIALS AND METHODS: In this study, liposomes containing polyethylene glycol encapsulated cisplatin (CDDP-L) were prepared. The action of CDDP-L on rat osteosarcoma and the enhancing action of caffeine on the antitumor effect of CDDP-L were evaluated. Using osteosarcoma-bearing rats, the retention of CDDP-L in the blood, its intratumor concentration, cytoreductive effect and the enhancing action of caffeine on its antitumor effect were examined. RESULTS: The liposomes were able to remain in the systemic circulation for a long time and to be concentrated in the osteosarcoma, but that action did not produce an effect corresponding to the quantity of cisplatin which was encapsulated reaching the tumor. In rats administered CDDP-L, it was discovered that the antitumor effect was not only enhanced by the coadministration of caffeine but also further enhanced when the dosing period of caffeine was increased. CONCLUSION: CDDP-L combined with caffeine treatment can produce better results for osteosarcoma.

Caffeine dose-dependently potentiates the antitumor effect of cisplatin on osteosarcomas.

BACKGROUND: Caffeine-assisted chemotherapy has been used in the treatment of osteosarcomas. However, there is little in vivo evidence for this treatment, and thus we sought to verify the dose and effect of caffeine in combination with cisplatin in osteosarcoma-bearing rats. MATERIALS AND METHODS: Seven-week-old male Fischer rats were transplanted with chemical carcinogen-induced osteosarcoma, selected lung metastatic lesions tumor block. The osteosarcoma-bearing rats were treated with saline, caffeine, cisplatin or cisplatin and caffeine. RESULTS: The most growth inhibition was observed in the co-administration group. When three different dosing schedules of caffeine were given, the extent of tumor inhibition was closely correlated with the average plasma concentration of caffeine. The cisplatin concentration in the tumor was significantly increased when caffeine was co-administered. CONCLUSION: This study confirms that a high concentration of caffeine (about 0.4 mM) is effective in enhancing the antitumor effects of cisplatin.

Caffeine-potentiated chemotherapy for patients with high-grade soft tissue sarcoma: long-term clinical outcome.

BACKGROUND: Caffeine, which has a DNA-repair inhibiting effect, enhances the cytocidal effects of anticancer drugs and radiation. The present study was performed to assess the efficacy of caffeine-potentiated chemotherapy for high-grade soft tissue sarcoma (STS). PATIENTS AND METHODS: A non-randomised prospective clinical trial was initiated for 90 patients with non-metastatic (stages II and III) or metastatic (stage IV) STS. Following doxorubicin or ifosfamide combined with caffeine, with or without radiotherapy, 88 patients were treated surgically. A radiographic and histological response to chemotherapy was assessed. Local-recurrence free, distant-metastasis free and overall survival were analyzed by multivariate analysis. RESULTS: Radiographic and histological response rates were 57.8% and 42%, respectively. The local recurrence rate was 23.7% in stages II and III and 13.6% in stage IV. Lung metastases newly developed in 21 (35.6%) patients at stages II and III. With a median follow-up period of 52 months, the overall 5-year cumulative survival rate at stages II and III was 80.7%. Local recurrence-free survival for the histological responders and distant metastasis-free survival for the radiographic responders at stages II and III were significantly improved compared to the non-responders (p=0.004 and p=0.034). Overall survival for the radiographic responders at all stages was significant longer than for the non-responders (p=0.009). CONCLUSION: Caffeine-potentiated chemotherapy resulted in a favourable radiographic response and prolonged overall survival of the patients at all stages.

Rapid determination method of caffeine and application to monitoring of caffeine-assisted chemotherapy.

Caffeine-assisted chemotherapy for bone and soft tissue tumours is very effective. However, high serum caffeine concentrations cause severe side effects, so monitoring of the serum level during therapy is important. For this purpose, a rapid determination method was established by high-performance liquid chromatography after solid-phase extraction. This method can measure caffeine and its three major metabolites in serum samples within 8 min. The mean serum caffeine concentrations of patients were 34.6+/-7.8, 54.5+/-11.9 and 73.0+/-12.8 microg/ml at 24, 48 and 72 h, respectively, after the start of a 1500 mg/m2/day continuous infusion for 72 h. The distribution volume of caffeine was 0.65+/-0.23 l/kg, and the total body clearance was 0.025+/-0.011 l/h/kg, which was one-third of the reported low dose clearance. The appropriate infusion rate was calculated to avoid severe side effects in the final phase of the infusion by using a one-compartment constant infusion model based on the serum levels measured at 24 and 48 h. Caffeine clearance did not correlate with the metabolite/caffeine ratio in serum at any time. It is concluded that individual monitoring with this method for the purpose of dose adjustment is useful for avoiding the side effects of caffeine-assisted chemotherapy.

Causative agent of vascular pain among photodegradation products of dacarbazine.

The photodegradation products of the anticancer drug, dacarbazine, cause adverse reactions including local venous pain when injected intravenously. In this study, we attempted to identify which of these products is responsible. We synthesized or purchased five photodegradation products of dacarbazine (dimethylamine, 5-diazoimidazole-4-carboxamide (Diazo-IC), 4-carbamoylimidazolium-5-olate, 5-carbamoyl-2-(4-carbamoylimidazol-5-ylazo)imidazolium-5-olate and 2-azahypoxanthine) and examined the pain reaction induced by their intraperitoneal administration in mice using an abdominal stretching or constriction assay. Only Diazo-IC clearly induced pain reaction in mice in a dose-dependent manner, the other products caused no pain reaction. The threshold concentration for pain reaction in mice was estimated to be about 0.1 mg mL-1. While diclofenac sodium significantly reduced acetic-acid-induced pain reaction in mice, it did not influence those induced by Diazo-IC. This result suggests that the mechanism of Diazo-IC-induced pain is different from that of acetic-acid-induced inflammatory pain. Dacarbazine itself produced marked relaxation of rat thoracic aorta strips in a concentration-dependent manner, but there was no difference between the activity of dacarbazine and its photo-exposed solution, so constriction or relaxation of blood vessels is unlikely to be a factor in the pain reaction. In conclusion, Diazo-IC generated by photodegradation of dacarbazine solution causes the side-effect of venous pain. Dacarbazine solution that has turned pink should not be used, because Diazo-IC is an intermediate in the formation of the reddish product, 5-carbamoyl-2-(4-carbamoylimidazol-5-ylazo)imidazolium-5-olate. Drip infusion preparations of dacarbazine should be shielded from light.