Pembrolizumab-induced secondary adrenal insufficiency due to adrenocorticotrophic hormone deficiency in a patient with non-small-cell lung carcinoma: a case report.

BACKGROUND: Pembrolizumab can cause immune-related adverse events such as adrenal insufficiency (AI). However, there is no consensus regarding appropriate monitoring of adrenal function during subsequent chemotherapy in patients who have received immune checkpoint inhibitors (ICIs) such as pembrolizumab. CASE PRESENTATION: In this report, we discuss the case of a 60s-year-old male patient with non-small cell lung cancer receiving chemotherapy who developed secondary AI due to adrenocorticotrophic hormone (ACTH) deficiency 8 months after the discontinuation of pembrolizumab, which was 17 months after the initiation of pembrolizumab immunotherapy. After 5 months of chemotherapy, he developed fever and diarrhoea, after which chemotherapy was discontinued. Thereafter, he was hospitalised owing to the development of general fatigue and anorexia. Although cortisol and ACTH levels were not measured during chemotherapy, they were measured before hospitalisation, and secondary AI was suspected. After admission, a detailed endocrine workup was performed, and the patient was diagnosed with secondary AI due to ACTH deficiency. Treatment with hydrocortisone was initiated, which markedly improved his general fatigue and anorexia. The patient showed no evidence of progressive disease 9 months after the discontinuation of pembrolizumab. CONCLUSIONS: Although rare, the possibility of AI should be considered in patients who have received ICIs when nonspecific symptoms develop during or after subsequent chemotherapy, and measurements of endocrine function (including cortisol and ACTH levels) should be performed.

Influence of Cytochrome P450 2C19 Genotype on Helicobacter pylori Proton Pump Inhibitor-Amoxicillin-Clarithromycin Eradication Therapy: A Meta-Analysis.

Background: Proton pump inhibitors (PPIs) are the first-line treatment for acid-related diseases. The pharmacokinetics and therapeutic efficacy of PPIs, however, are influenced by genetic factors such as variants in genes encoding drug-metabolizing enzymes (e.g., cytochrome P450 2C19 [CYP2C19]) and drug transporters. We performed a meta-analysis to evaluate the influence of CYP2C19 genotype and PPI class, PPI dose, treatment duration and clarithromycin dose on the cure rate of PPI-containing Helicobacter pylori eradication therapy. Methods: Randomized control trials (RCTs) investigating cure rates using a PPI-amoxicillin-clarithromycin regimen among different CYP2C19 genotypes through May 2021 were included. Results: A total of 25 studies (5,318 patients) were included. The overall eradication rate in the intention-to-treat analysis was 79.0% (3,689/4,669, 95% confidence interval [CI]: 77.8-80.2%), and that in CYP2C19 extensive metabolizers (EMs), intermediate metabolizer (IMs) and poor metabolizers (PMs) was 77.7% (1,137/1,464, 95% CI: 75.3-79.6%), 81.2% (1,498/1,844, 95% CI: 79.3-83.0%) and 86.8% (644/742, 95% CI: 83.9-88.9%), respectively. Meta-analysis showed that the relaTakashitive risk of failed eradication in CYP2C19 EMs compared with IMs and PMs was 1.21 (95% CI: 1.06-1.39, P = 0.006) and 1.57 (95% CI: 1.27-1.94, P < 0.001), respectively, in the fixed-effects model. The cure rate of omeprazole and lansoprazole-containing eradication regimens differed among CYP2C19 genotypes (P < 0.05), while that of rabeprazole and esomeprazole-containing regimens was similar. Conclusion: The cure rates of PPI-amoxicillin-clarithromycin H. pylori eradication regimen, especially those containing omeprazole and lansoprazole, differ among CYP2C19 genotypes. Therefore, selection of a second-generation PPI or tailored treatment may achieve higher eradication rates than first-generation PPI-amoxicillin-clarithromycin triple regimen.

Development of Japanese Versions of the Control Preferences Scale and Information Needs Questionnaire: Role of Decision-Making and Information Needs for Japanese Breast Cancer Patients.

PURPOSE: The importance of shared decision-making (SDM) between physicians and patients is increasingly recognized. In Japan, patients have shown more willingness to participate in treatment if medical professionals provide sufficient information; however, relationships between physicians and patients have traditionally been asymmetric, with patients accepting information from physicians without discussion. To explore the benefits of SDM in cancer treatment, including confidence in treatment decisions, satisfaction with treatment, and trust in healthcare providers, this study developed Japanese versions of the Control Preference Scale (CPS) and Information Needs Questionnaire (INQ). PATIENTS AND METHODS: Reliability and validity of the CPS and INQ were tested with 49 breast cancer patients. RESULTS: The CPS showed good test-retest reliability (kappa coefficient: 0.61, weighted kappa coefficient: 0.61, Kendall's tau coefficient: 0.61) and acceptable criterion validity. The INQ showed adequate consistency; the mean number of circular triads and coefficient of consistency were 3 (range 0-19) and 0.9 (range 0.37-1), respectively. Using the CPS and INQ to identify patients' roles in decision-making and information needs, results further suggested that breast cancer patients in Japan want to participate in SDM. Medical issues, including disease spread and cure, were found to be of high interest, while social and psychological issues, including sexual attractiveness, genetic risk, and family impact, tended to be low. CONCLUSION: The Japanese CPS and INQ can be used to assess patients' needs to improve care. Further, as patients' information needs change along the care trajectory, these tools should be used throughout treatment.

Individual Lymphocyte Sensitivity to Steroids as a Reliable Biomarker for Clinical Outcome after Steroid Withdrawal in Japanese Renal Transplantation.

Recently, steroid reduction/withdrawal regimens have been attempted to minimize the side effects of steroids in renal transplantation. However, some recipients have experienced an increase/resumption of steroid administrations and acute graft rejection (AR). Therefore, we investigated the relationship between the individual lymphocyte sensitivity to steroids and the clinical outcome after steroid reduction/withdrawal. We cultured peripheral blood mononuclear cells (PBMCs) isolated from 24 recipients with concanavalin A (Con A) in the presence of methylprednisolone (MPSL) or cortisol (COR) for four days, and the 50% of PBMC proliferation (IC50) values and the PBMC sensitivity to steroids were calculated. Regarding the experience of steroid increase/resumption and incidence of AR within one year of steroid reduction/withdrawal, the IC50 values of these drugs before transplantation in the clinical event group were significantly higher than those in the event-free group. The cumulative incidence of steroid increase/resumption and AR in the PBMC high-sensitivity groups to these drugs before transplantation were significantly lower than those in the low-sensitivity groups. These observations suggested that an individual's lymphocyte sensitivity to steroids could be a reliable biomarker to predict the clinical outcome after steroid reduction/withdrawal and to select the patients whose dose of steroids can be decreased and/or withdrawn after transplantation.

Pharmacodynamic Drug-Drug Interaction on Human Peripheral Blood Mononuclear Cells Between Everolimus and Tacrolimus at the Therapeutic Concentration Range in Renal Transplantation.

BACKGROUND Everolimus (EVL) plus tacrolimus (TAC) therapy is effective and safe in renal transplantation. However, the pharmacokinetic and pharmacodynamic information for EVL combined with TAC is limited. We investigated the pharmacodynamic drug-drug interaction between EVL and TAC at their therapeutic concentration range. MATERIAL AND METHODS Isolated peripheral blood mononuclear cells (PBMCs) from 22 healthy participants aged 22 to 24 years were cultured with concanavalin A (Con A) in the presence of EVL and/or TAC for 4 days, and the proliferation rate of the PBMCs was calculated. RESULTS TAC promoted the inhibitory efficacy of EVL against the mitogen-activated proliferation of PBMCs at the EVL therapeutic concentration range. When 0.175 ng/mL or more of TAC was combined with 30 ng/mL or more of EVL, the antagonistic effect of TAC on the inhibitory efficacy of EVL against the mitogen-activated proliferation of PBMCs was observed. Conversely, when 0.4 ng/mL TAC and 10 ng/mL or more of EVL were combined, the antagonistic effect of EVL on the inhibitory efficacy of TAC against the mitogen-activated proliferation of PBMCs was observed. CONCLUSIONS The pharmacodynamic synergistic efficacy of EVL and TAC in combination on mitogen-activated PBMCs was evident at the therapeutic concentration range, which is used in renal transplantation. However, these drugs antagonize each other to suppress the proliferation of activated PBMCs at concentrations higher than those clinically used.

Investigation of Oral Preparation That Is Expected to Improve Medication Administration: Preparation and Evaluation of Oral Gelling Tablet Using Sodium Alginate.

We investigated the preparation of a gelling tablet that swells and forms a gel upon absorbing water, and hence would be easy for patients to swallow. We prepared naked tablets and compressed coated tablets by the direct tableting or wet granule-compression methods, using the commonly prescribed drug acetaminophen (AA) and sodium alginate (AG) as a thickening agent. The tablets quickly absorbed water, had favorable gelling properties, low adhesiveness, appropriate drug dissolution profile, and at the same time, were easy to swallow. In the case of naked tablets, water absorption increased upon granulation, but gelling of AG interfere when AA and AG were present together. There was no change in the adhesiveness, and more than 30 min were required to achieve a 25% dissolution ratio. Compressed coated tablets that were made with AA in the inner layer and granulated AG in the outer layer showed improved dissolution behavior, it was about 90% dissolution ratio in 30 min, owing to the water absorption property of AG, and decreased adhesiveness. In this case, there was a difference in the outer layer thickness. As the outer layer amount increased, dissolution slowed, but it did not depend on the compression pressure. Our gelling tablet can be prepared by using AA (main drug) in the inner layer and an appropriate thickness of granulated AG in the outer layer of compressed coated tablets.

Preparation of an oral acetaminophen film that is expected to improve medication administration: Effect of polyvinylpyrrolidone on physical properties of the film.

This study investigated the effect of polyvinylpyrrolidone (PVP) on a film containing carboxymethyl cellulose sodium (CMC) as a matrix to improve surface roughness caused by drug recrystallization. Acetaminophen (AA) was used as the model drug. Recrystallization is a problem encountered during the preparation of films that contain high drug doses, making them difficult to take. A film that does not disintegrate for clinical applications requires a smooth surface, moderate strength and elasticity, and a low level of adhesiveness to facilitate taking of the medication. Addition of PVP to the film formulation made the surface significantly smoother, and it was independent of the compounding method. Smooth films were obtained when the CMC concentration was kept constant and the amount of PVP was increased, but it also increased the adhesiveness and strength, and decreased the elasticity of the films. When high polymer concentration was kept constant and the ratio of CMC and PVP was varied, the films with smaller amounts of PVP tended to have a smoother surface and less adhesiveness. However, when the amount of PVP was reduced, the film strength increased and elasticity decreased. The amount of PVP had a negligible effect on drug dissolution behavior, making it useful for preparation of the AA film. However, it is necessary to determine the compounding method and the PVP load considering the adhesiveness, strength, and elasticity of the films.

Prevalence of Autoantibodies and the Efficacy of Immunotherapy for Autoimmune Cerebellar Ataxia.

OBJECTIVE: Autoimmune cerebellar ataxias were recently reported to be treatable. However, the proportion of patients with cortical cerebellar atrophy of unknown etiology with autoimmune-associated cerebellar ataxia and the actual effectiveness of immunotherapy in these diseases remain unknown. METHODS: We measured the level of autoantibodies (including anti-gliadin antibody, anti-glutamic acid decarboxylase (GAD) antibody, and anti-thyroid antibody) in 58 Japanese patients with cerebellar ataxia, excluding those with multiple system atrophy, hereditary spinocerebellar ataxia, cancer, or those who were receiving phenytoin, and the efficacy of immunotherapy was assessed. RESULTS: Thirty-one of 58 (53%) patients were positive for anti-GAD antibody, anti-gliadin antibody, or anti-thyroid antibody. Seven of the 12 anti-gliadin antibody-positive patients, three of the four anti-GAD antibody-positive patients, and three of the six anti-thyroid antibody-positive patients responded well to immunotherapy, indicating that 59% of patients with ataxia-associated antibody-positive cerebellar ataxia undergoing immunotherapy responded well. CONCLUSION: Some patients with cerebellar ataxia have autoimmune conditions and diagnosing autoimmune cerebellar ataxia is therefore an important component in the care of patients with this disease entity.

Assessment of Cancer-Related Fatigue, Pain, and Quality of Life in Cancer Patients at Palliative Care Team Referral: A Multicenter Observational Study (JORTC PAL-09).

INTRODUCTION: Cancer-related fatigue greatly influences quality of life in cancer patients; however, no specific treatments have been established for cancer-related fatigue, and at present, no medication has been approved in Japan. Systematic research using patient-reported outcome to examine symptoms, particularly fatigue, has not been conducted in palliative care settings in Japan. The objective was to evaluate fatigue, pain, and quality of life in cancer patients at the point of intervention by palliative care teams. MATERIALS AND METHODS: Patients who were referred to palliative care teams at three institutions and met the inclusion criteria were invited to complete the Brief Fatigue Inventory, Brief Pain Inventory, and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 15-Palliative. RESULTS: Of 183 patients recruited, the majority (85.8%) were diagnosed with recurrence or metastasis. The largest group (42.6%) comprised lung cancer patients, of whom 67.2% had an Eastern Cooperative Oncology Group Performance Status of 0-1. The mean value for global health status/quality of life was 41.4, and the highest mean European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 15-Palliative symptom item score was for pain (51.0). The mean global fatigue score was 4.1, and 9.8%, 30.6%, 38.7%, and 20.8% of patients' fatigue severity was classified as none (score 0), mild (1-3), moderate (4-6), and severe (7-10), respectively. DISCUSSION: Cancer-related fatigue, considered to occur more frequently in cancer patients, was successfully assessed using patient-reported outcomes with the Brief Fatigue Inventory for the first time in Japan. Results suggested that fatigue is potentially as problematic as pain, which is the main reason for palliative care.

Preparation and evaluation of gelling granules to improve oral administration.

We investigated the preparation of oral granules that are solid when stored and that will swell and gel via water absorption, to address problems experienced by patients when taking medication. Important physical properties of gelling granules include elasticity that is normally smooth, quick water absorption and swelling properties that allow easy swallowing. We selected gelatin (GEL), succinylated gelatin (SUC-GEL) and ι-carrageenan (CAR) as matrix polymers that can undergo gelation at room temperature or at cold temperatures. Saccharide and polyethylene glycol (PEG) were added to prepare the experimental granules. The best matrix gelling granule was SUC-GEL. When xylitol (XYL), sorbitol (SOR) and maltitol (MAL) were added, elasticity was improved, and PEG improved the granule's water absorption behavior, which is an important element involved in gelation. The best granules were prepared by selecting SUC-GEL as the matrix and adding a small amount of PEG and XYL in amounts equal to that of SUC-GEL.

Synergistic Effects of Calcineurin Inhibitors and Steroids on Steroid Sensitivity of Peripheral Blood Mononuclear Cells.

The steroid receptor (SR) complex contains FKBP51 and FKBP52, which bind to tacrolimus (TAC) and cyclophilin 40, which, in turn, bind to cyclosporine (CYA); these influence the intranuclear mobility of steroid-SR complexes. Pharmacodynamic interactions are thought to exist between steroids and calcineurin inhibitors (CNIs) on the SR complex. We examined the effect of CNIs on steroid sensitivity. Methylprednisolone (MPSL) sensitivity was estimated as the concentration inhibiting mitosis in 50% (IC50) of peripheral blood mononuclear cells and as the area under the MPSL concentration-proliferation suppressive rate curves (CPS-AUC) in 30 healthy subjects. MPSL sensitivity was compared between the additive group (AG) as the MPSL sensitivity that was a result of addition of the proliferation suppressive rate of CNIs to that of MPSL and the mixed culture group (MCG) as MPSL sensitivity of mixed culture with both MPSL and CNIs in identical patients. IC50 values of MPSL and cortisol sensitivity were examined before and 2 months after CNI administration in 23 renal transplant recipients. IC50 and CPS-AUC values of MPSL were lower in the MCG than in the AG with administration of TAC and CYA. The CPS-AUC ratio of MCG and AG was lower in the TAC group. IC50 values of MPSL and cortisol tended to be lower after administration of TAC and CYA, and a significant difference was observed in the IC50 of cortisol after TAC administration. Steroid sensitivity increased with both TAC and CYA. Furthermore, TAC had a greater effect on increasing sensitivity. Thus, concomitant administration of CNIs and steroids can increase steroid sensitivity.

Preferences for pharmacist counselling in patients with breast cancer: a discrete choice experiment.

With the shift of a large proportion of cancer chemotherapy recipients to ambulatory care, the role of hospital pharmacists has changed, and their provision of information is essential care for cancer patients. There is little research on pharmacist-patient relations, particularly about pharmacist counselling, in Japan. To meet patients' needs, pharmacist counselling should be optimized. Here, breast cancer patients' preferences for pharmacist counselling were assessed using a discrete choice experiment. Bayesian nonlinear optimal methodology was employed to obtain six attributes (attitude of pharmacist, quality of information, explanation of side effects, frequency of pharmacist counselling before starting chemotherapy, cost of pharmacist counselling, and follow-up with the pharmacist after starting chemotherapy) of two to three levels each. The attributes and levels were used to create 12 hypothetical scenarios that were divided into two questionnaires of six choice sets each. Two hundred eighty participants were randomly assigned to complete one of these questionnaires (blocks). Attributes were analyzed by conditional logit model to determine significant predictors of patient preferences. The responses of 278 patients to 1667 scenarios were analyzed. Attitude of pharmacist, quality of information, cost of pharmacist counselling, and follow-up with the pharmacist after starting chemotherapy were significant predictors of patient preferences, with quality of information receiving the highest priority. Thus patients receiving pharmacist counselling before starting chemotherapy prefer to interact with a pharmacist with a friendly, interested attitude who provides individualized information. Further research is needed to elucidate the information that Japanese patients consider most important and to enhance pharmacist-patient communication.

Clinical significance of peripheral blood lymphocyte sensitivity to glucocorticoids for the differentiation of high-risk patients with decreased allograft function after glucocorticoid withdrawal in renal transplantation.

PURPOSE: A reliable biomarker to differentiate high-risk recipients who will experience a decrease in allograft function after glucocorticoid withdrawal has not been established in renal transplantation. We examined the clinical significance of peripheral blood lymphocyte sensitivity to glucocorticoids in vitro for the differentiation of the high-risk patients after glucocorticoid reduction/withdrawal in renal transplant recipients. METHODS: The study included 44 renal transplant recipients with stable allograft function. Peripheral lymphocyte responses to suppressive effects of cortisol, methylprednisolone, cyclosporine, and tacrolimus in mitogen assay procedures in vitro were examined. Clinical outcome after glucocorticoid reduction/withdrawal was retrospectively compared between recipients with lymphocytes normally sensitive to the drugs and those with hyposensitivity. The receiver-operating characteristic (ROC) curve analysis was undertaken for setting the cutoff IC50 values of the drugs against the T cell mitogen-induced lymphocyte proliferation to differentiate the high-risk recipients with decreased allograft function after glucocorticoid withdrawal. FINDINGS: The median (range) IC50 value for cortisol in the recipients who showed decreased renal function due to glucocorticoid withdrawal was 10,000 (570.9-72,279.3) ng/mL (n = 9), which was significantly higher than the value of 351.6 (2.0-10,000) ng/mL in the recipients who had not experienced glucocorticoid withdrawal symptoms (n = 35) (P < 0.001). Similarly, the median (range) IC50 value for methylprednisolone in the recipients who showed decreased renal function after glucocorticoid withdrawal was 69.1 (21.5-1442.7) ng/mL (n = 9), which was significantly higher than the value of 13.8 (0.7-1000) ng/mL in the recipients who had not experienced glucocorticoid withdrawal symptoms (n = 30) (P < 0.003). In contrast, there was no significant difference in the median IC50 values of cyclosporine and tacrolimus between the 2 recipient subgroups. The ROC curve analyses for the IC50 values of the immunosuppressive drugs estimated the cutoff value of cortisol and methylprednisolone to be 3580.0 and 21.5 ng/mL, respectively. The ROC AUCs for cortisol and methylprednisolone were 0.83 and 0.84, respectively. According to the cutoff IC50 value, the incidence of decreased allograft function in the low cortisol sensitivity (IC50 >3580.0 ng/mL) subgroup was 7 of 13 patients, which was significantly higher than that of the higher sensitivity subgroup of 2 of 31 (P = 0.0012). A similar case was observed using the cutoff IC50 value of methylprednisolone (P = 0.0012), whereas recipient grouping according to the cutoff IC50 values of cyclosporine and tacrolimus failed to differentiate the high-risk recipients with decreased allograft function after glucocorticoid withdrawal. IMPLICATIONS: Glucocorticoid pharmacodynamics in lymphocytes of individual patient origin is a reliable biomarker for differentiation of renal transplant recipients who will experience a safe reduction/withdrawal of glucocorticoid.

Development and validation of the Japanese version of the Decisional Conflict Scale to investigate the value of pharmacists' information: a before and after study.

BACKGROUND: The information provided in patient-centered care and shared decision-making influences patients' concerns and adherence to treatment. In the decision-making process, patients experience decisional conflict. The Decisional Conflict Scale (DCS) is a 16-item, self-administered questionnaire consisting of 5 subscales developed to assess patients' decisional conflict. This study aimed to develop the Japanese version of the DCS and to clarify the influence of the information provided by pharmacists' on decisional conflict among patients with cancer. METHODS: We developed the Japanese version of the DCS by using the forward-backward translation method. One hundred patients who were recommended a new chemotherapy regimen were recruited. The psychometric properties of the Japanese DCS, including internal consistency, convergent validity, discriminant validity, and construct validity, were examined. We assessed the decisional conflict of patients before and after the pharmacists' provision of information. RESULTS: Ninety-four patients, predominately female, with an average age of 58.1 years were sampled. The scores on the 5 subscales of the DCS showed high internal consistency (Cronbach's alpha = 0.84-0.96). Multi-trait scaling analysis and cluster analysis showed strong validity. The mean total DCS score decreased significantly from 40.2 to 31.7 after patients received information from the pharmacists (p < 0.001, paired t-test). Scores on all 5 subscales, namely, uncertainty, informed, values clarity, support, and effective decision, also significantly improved (p < 0.001 for all categories, paired t-test). CONCLUSIONS: The psychometric properties of the Japanese version of the DCS are considered appropriate for it to be administered to patients with cancer. Pharmacists' provision of information was able to decrease decisional conflict among patients with cancer who were recommended a new chemotherapy regimen.

Determinants affecting quality of life: implications for pharmacist counseling for patients with breast cancer in Japan.

Although pharmacist counseling assumes an important role in the clinical setting, oncology pharmacy practitioners worldwide currently lack adequate guidance. This study aimed to identify the determinants and causal relationships that affect quality of life (QOL) in breast cancer patients before adjuvant systemic therapy for improving pharmacist counseling and guidance. This study analyzed 93 postoperative patients with breast cancer before pharmacist counseling for adjuvant systemic therapy. Patients were asked to complete questionnaires to assess QOL (the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 [EORTC QLQ-C30] and its breast cancer module [EORTC QLQ-BR23]) before pharmacist counseling. We analyzed factors affecting QOL by stepwise multiple linear regression analysis and evaluated causal association using path analysis. In the multiple linear regression model using variables selected by stepwise analysis, the factors affecting global health status (GHS)/QOL included fatigue, emotional functioning, systemic therapy side effects, future perspectives, and appetite loss. In the path analysis model, GHS/QOL were strongly influenced by fatigue directly; and emotional functioning, directly and indirectly via other factors. Our results indicated that fatigue and emotional functioning are strong factors affecting QOL. These factors may be able to predict poor QOL before initiating adjuvant systemic therapy. Thus, our findings suggest that these factors may be potentially useful for pharmacist counseling at the beginning of adjuvant systemic therapy.

Higher Sensitivity of Peripheral Blood Lymphocytes to Endogenous Glucocorticoid in Renal Transplant Recipients Treated With Tacrolimus, as Compared to Those Treated With Cyclosporine.

Lymphocyte sensitivity to endogenous glucocorticoid cortisol could be a biological marker for safe reduction and withdrawal of steroids in renal transplant recipients. We compared peripheral lymphocyte sensitivity with cortisol between transplant recipients treated with tacrolimus (Tac) and those treated with cyclosporine. The suppressive efficacies of cortisol against T-cell mitogen-stimulated proliferation of peripheral lymphocytes were investigated in 44 renal transplant patients, who either had reduced or been withdrawn from steroid treatment. Twenty of the 44 patients were treated with Tac, and the other 24 patients were treated with cyclosporine A (CyA). The lymphocyte sensitivity to cortisol was compared between these two patient groups. The cortisol IC50 values in the Tac and CyA groups were 0.09 ± 0.12 and 14.2 ± 12.7 ng/ml, respectively. Lymphocyte sensitivity to cortisol in the Tac-treated group was significantly higher than that in the CyA-treated group (p = 0.0283). On the other hand, incidences of steroid withdrawal syndrome and increases in serum creatinine concentration were not significantly different between the Tac and CyA groups. Lymphocyte sensitivity to cortisol was higher in the Tac-treated patients than that in the CyA-treated ones. Since the cortisol sensitivity of peripheral lymphocytes is suggested to be a predictive marker for safe steroid withdrawal, Tac administration shows promise in aiding successful withdrawal of steroid treatment in long-term renal transplant recipients.

Steroid withdrawal based on lymphocyte sensitivity to endogenous steroid in renal transplant recipients.

Though steroid withdrawal is done in many renal transplant recipients, some patients must restart steroids. Little report has investigated steroid withdrawal under pharmacodynamic monitoring. We assessed lymphocyte sensitivity to endogenous cortisol as a biomarker for determining the safety of steroid withdrawal in renal transplant patients, as we hypothesized that patients hyposensitive to cortisol could not be sufficiently immunosuppressed by their intrinsic cortisol as a substitute for the reduced or withdrawn steroid. Lymphocyte sensitivity to cortisol was examined in 30 long stable renal transplant recipients. Lymphocyte sensitivity to cortisol and its relationship with the clinical outcome after steroid reduction and withdrawal was investigated. The lymphocyte sensitivities to cortisol were estimated as IC(50) of lymphocyte blastogenesis. The lymphocyte proliferation rate for concentration of serum cortisol compared between incident and non-incident groups. Serum creatinine levels (S-Cr) increased in a significantly higher number of patients hyposensitive to cortisol (IC(50)≧10000 ng/ml) than in normally sensitive patients (IC(50)<10000 ng/ml). The incidences of steroid withdrawal syndrome and necessity for increasing steroid dose or restarting steroid administration were also higher in the patients hyposensitive to cortisol. The patients in whom the lymphocyte proliferation rate was less than 60% did not show increase in S-Cr, experience steroid withdrawal symptoms, or require an increase in the steroid dose or restart of steroid administration. The patients who have the normal IC(50) values of cortisol, can withdraw steroid more safely. The lymphocyte sensitivity to cortisol may be a useful biomarker for selecting patients who can sustain steroid withdrawal.

Comparative study of the cellular pharmacodynamics of calcineurin inhibitors between patients with chronic renal failure awaiting renal transplantation and cirrhosis patients awaiting liver transplantation.

The in vitro response of peripheral blood mononuclear cells (PBMCs) to the suppressive effects of calcineurin inhibitors is known to correlate with the clinical efficacy of drugs used in renal transplantations. The present study was conducted to examine the differences of PBMC responses to calcineurin inhibitors between chronic renal failure (CRF) patients awaiting renal transplantation and cirrhosis patients awaiting liver transplantation. The study included 99 CRF patients awaiting renal transplantation and 27 cirrhosis patients awaiting liver transplantation. Twenty milliliters of venous blood was taken 1-7 days before transplantation. The in vitro drug concentrations giving 50% inhibition of PBMC blastogenesis stimulated with concanavalin A (IC(50)s) were calculated. The suppressive effects of tacrolimus against PBMC blastogenesis were more than 10-100 times stronger than those of cyclosporine. The median IC(50) value for cyclosporine against the CRF PBMCs was not significantly different from the median IC(50) value against the cirrhosis PBMCs. In contrast, tacrolimus sensitivity in cirrhosis PBMCs is approximately seven times higher than that in CRF PBMCs. The median IC(50) value for tacrolimus against cirrhosis PBMCs was significantly lower and therefore the effect was stronger in comparison to the CRF PBMCs (p < 0.001). These data suggest that the PBMCs of cirrhosis patients, in comparison to those of CRF patients, are highly sensitive to the suppressive effect of tacrolimus. However, PBMC sensitivity to cyclosporine was not significantly different between the CRF and cirrhosis patients. These observations raise the possibility that treatment with tacrolimus, rather than cyclosporine, may therefore be a better choice to reduce the risks of allograft rejection in liver transplantation.

Clinical significance of the cellular pharmacodynamics of tacrolimus in living-donor liver transplantation.

Successful immunosuppressive therapy is critical for liver transplantation; however, a considerable number of patients experience fatal rejection or alternatively exhibit serious infection resulting from excessive immunosuppression. The in vitro tacrolimus response of peripheral blood mononuclear cells (PBMCs) before transplantation was compared to the clinical outcome up to 4 weeks after operation in 28 living-donor liver transplant recipients treated with tacrolimus. The tacrolimus IC(50) values against concanavalin A-induced PBMC blastogenesis in vitro were calculated. These recipients were classified into two groups with the mean tacrolimus IC(50) (0.18 ng/ml) as the cutoff point, after which the clinical outcome between the patient groups was compared. The allograft rejection incidence in the low-sensitivity group (IC(50) < 0.18 ng/ml; n = 16) was 6/12 (50.0%), which was significantly higher than the incidence of 2/16 (12.5%) in the high-sensitivity group (IC(50) > 0.18 ng/ml; n = 12) (p = 0.0297). In contrast, the infection incidence in the high-sensitivity group was 6/16 (37.5%), which was significantly higher than that of the low-sensitivity group (1/12; 8.3%) (p = 0.0401). These data suggest that patients exhibiting a low PBMC sensitivity to tacrolimus have a risk of rejection, whereas highly sensitive patients have a risk of infection in living-donor liver transplantations under tacrolimus therapy.

Chemotherapy with low-dose capecitabine as palliative treatment in a patient with metastatic breast cancer: a case report.

Chemotherapeutic agents are rarely used for symptom management in patients under palliative care setting. This is because chemotherapeutic agents not only have limited efficacy in palliative treatment but are also known to exert severe adverse effects. We describe our experience with a patient with metastatic breast cancer who was successfully treated with low-dose capecitabine, without the development of any severe toxicities and with significant improvement in activities of daily living (ADL) and quality of life (QOL).The patient, a 43-year-old female, had breast cancer with liver, bone, and cutaneous metastases. She visited our clinic after a year-long hiatus during which she underwent alternative therapy. She presented with ulcerated lesions on the anterior chest and dyspnea due to malignant pleural effusion. After treatment for the latter, we administered capecitabine (600 mg/day) in accordance with the wishes of the patient and her attendants. The ulcerated lesions on the anterior chest, dyspnea, ADL and QOL improved significantly, without the development of any serious adverse effects. The findings of this case indicate that chemotherapy in the form of low-dose capecitabine monotherapy may be considered in patients under palliative care setting.