The lymphocyte/monocyte ratio predicts the efficacy of isatuximab plus pomalidomide in multiple myeloma patients.

BACKGROUND: Isatuximab, an anti-CD38 antibody, has been widely used in treatments for patients with relapsed/refractory multiple myeloma (MM). Despite its high efficacy, not all patients achieve a lasting therapeutic response with isatuximab. OBJECTIVE: We tried to identify biomarkers to predict the effectiveness of isatuximab by focusing on the host's immune status before treatment. METHODS: We retrospectively analyzed the cases of 134 relapsed/refractory MM patients in the Kansai Myeloma Forum database who had received only a first isatuximab treatment. RESULTS: Among the 134 patients, an isatuximab, pomalidomide and dexamethasone (Isa-PD) regimen, isatuximab, carfilzomib and dexamethasone (Isa-KD) regimen and isatuximab and/or dexamethasone (Isa-D) regimen were used in 112, 15 and 7 patients, respectively. The median age at treatment, number of prior treatment regimens, and progression-free survival (PFS) were 71, 6, and 6.54 months, respectively. Multivariate analysis showed that the PFS under the Isa-PD regimen was longer in patients with higher lymphocyte/monocyte ratio (LMR ≥ 4), fewer prior treatment regimens (< 6), and no use of prior daratumumab treatment. The OS under the Isa-PD regimen was longer in patients with higher white blood cell counts (WBC counts ≥ 3000/µL) and higher LMR. The PFS under the Isa-D regimen was longer in patients with fewer prior treatment regimens in univariate analysis, but no parameters were correlated with PFS/OS under the Isa-KD regimen. CONCLUSION: We found that the patients with higher LMR (≥ 4) could obtain longer PFS and OS under the Isa-PD regimen. Other cohort studies of isatuximab treatment might be necessary to substantiate our results.

Efficacy of elotuzumab for multiple myeloma deteriorates after daratumumab: a multicenter retrospective study.

Elotuzumab-based regimens are sometimes selected for multiple myeloma treatment after daratumumab-based regimens. However, there has been insufficient discussion on the efficacy of elotuzumab after daratumumab. We used Kansai Myeloma Forum registration data in a multicenter retrospective evaluation of the efficacy of elotuzumab after daratumumab. Overall survival (OS) rate and time to next treatment (TTNT) were significantly worse in the cohort given elotuzumab after daratumumab (Dara cohort, n = 47) than in the cohort with no history of daratumumab administration before elotuzumab (No-Dara cohort, n = 80, OS: P = 0.03; TTNT: P = 0.02; best response: P < 0.01). In the Dara cohort, OS and TTNT rates were worse with sequential elotuzumab use after daratumumab than with non-sequential (OS: P = 0.02; TTNT: P = 0.03). In patients given elotuzumab < 180 days after daratumumab, OS (P = 0.08) and best response (P = 0.21) tended to be worse, and TTNT was significantly worse (P = 0.01), than in those given elotuzumab after ≥ 180 days. These findings were confirmed by subgroup analyses and multivariate analyses. Monoclonal-antibody-free treatment might be preferable after daratumumab-based regimens. If possible, elotuzumab-based regimens should be considered only ≥ 180 days after daratumumab use.

An observational study of once-weekly carfilzomib in patients with multiple myeloma in Japan (Weekly-CAR study).

Background: The ARROW study demonstrated that once-weekly carfilzomib and dexamethasone (wKd) therapy significantly prolonged progression-free survival compared with twice-weekly carfilzomib and dexamethasone therapy in relapsed or refractory multiple myeloma patients. Aim: To describe the treatment patterns, effectiveness and safety of wKd therapy in real-world settings in Japan. Methods: We investigated data from the medical records of 126 Japanese patients with relapsed or refractory multiple myeloma. Results: The overall response rate was 66.3%. The median progression-free survival was 9.5 months. The incidence of treatment-emergent adverse events of any grade and grade ≥3 were 45.8 and 20.8%, respectively. Conclusion: There were no new or unexpected safety signals in this study. This study demonstrated the effectiveness and safety profiles of wKd therapy in Japan.

Carfilzomib became available for daily clinical practice as a drug for cancer of bone marrow (multiple myeloma) that comes back or does not respond to previous drug (relapsed or refractory). This drug was approved in the USA in 2012, and in Japan in 2016. In this study, we looked at how once-weekly carfilzomib works and how safe it is in real-life situations in Japan. We screened 126 patients with relapsed or refractory multiple myeloma in Japan. The median age of the patients was 70 years, with 25% being over 75 years. This study also included some patients who were not in the best overall health, had a history of many treatments or had heart complications. In 66.3% of patients, the cancer had disappeared or the extent of the cancer had reduced after treatment. Side effects and serious side effects occurred in 45.8 and 14.2% of patients, respectively. The most common side effects were low levels of blood platelets (9.2%), high blood pressure (5.8%), loose or watery stools (5.0%), fever (5.0%), and low levels of red blood cells (4.2%). Heart disorders occurred in five patients. But all patients recovered or improved with treatment such as blood pressure lowering drugs and diuretics. These results showed that once-weekly carfilzomib works well and is safe in real-world settings in Japan. This information can help us think about how to pick the right patients and handle heart disease risks when using carfilzomib treatment.

Comparison of pneumonia severity scores for COVID-19 patients with the Omicron variant.

INTRODUCTION: We demonstrated that there was a significant relationship between the severity measured using the A-DROP scoring system and the mortality rate in patients with COVID-19 community-acquired pneumonia (CAP) in the ancestral strain, Alpha variant, and Delta variant. We investigated the usefulness of the A-DROP scoring system in SARS-CoV-2 Omicron variant CAP and compared it with severity scores, the Pneumonia Severity Index (PSI) and CURB-65 score. METHODS: We analyzed a total of 547 patients with COVID-19 CAP Omicron variant; 198 cases were the BA.1 subvariant, 127 cases were the BA.2 subvariant, and 222 cases were the BA.5 subvariant, respectively. RESULTS: The mortality rates in patients with COVID-19 CAP among the three Omicron subvariants were identical in each pneumonia severity group. The mortality rate in patients with the Omicron variant was 0 % in patients classified with mild disease, 0.6 % in those with moderate disease, 10.4 % in those with severe disease, and 34.8 % in those with extremely severe disease. The mortality rate in patients with COVID-19 CAP increased depending on the severity classified according to the A-DROP system in each of the Omicron subvariants (Cochran-Armitage trend test; p < 0.001). The values of the area under the curve in Receiver Operating Characteristic analysis for prediction of 30-day mortality was 0.881, 0.879, and 0.863 for A-DROP, PSI, and CURB-65, respectively. There were no significant differences in the predictive ability of each pneumonia severity score. CONCLUSIONS: Our results demonstrated that the A-DROP scoring system is useful for predicting mortality in patients with COVID-19 CAP.

Fostamatinib for the treatment of Japanese patients with primary immune thrombocytopenia: A phase 3, placebo-controlled, double-blind, parallel-group study.

Fostamatinib, a spleen tyrosine kinase inhibitor, has been approved for the treatment of chronic primary immune thrombocytopenia (ITP) in the United States, Canada and some European countries. We conducted a phase 3, placebo-controlled, double-blind, parallel-group study to evaluate the efficacy and safety of fostamatinib in Japanese patients with primary ITP. Thirty-four patients were randomised to fostamatinib (n = 22) or placebo (n = 12) at 100-150 mg twice a day for 24 weeks. Stable responses (platelet ≥50 000/µl at ≥4 of the 6 visits from weeks 14 to 24) were observed in eight (36%) patients on fostamatinib and in none of the patients on placebo (p = 0.030). Overall responses (platelet ≥50 000/µl at ≥1 of the 6 visits from weeks 2 to 12) were seen in 10 (45%) patients on fostamatinib and in none of the patients on placebo (p = 0.006). Patients on fostamatinib required rescue medication less often and experienced fewer bleeding symptoms than patients on placebo. Adverse events observed were mild or moderate and were manageable. No new safety signals were identified in Japanese patients with ITP.

Real-world data from yttrium-90 ibritumomab tiuxetan treatment of relapsed or refractory indolent B-cell non-Hodgkin's lymphoma: J3Zi Study.

Yttrium-90 ibritumomab tiuxetan (90YIT) is a radioimmunotherapy agent in which the radioisotope yttrium-90 is bound to ibritumomab via tiuxetan as a chelating agent, and is used for relapsed or refractory low-grade B-cell non-Hodgkin's lymphoma (rr-B-NHL). We conducted a joint study to evaluate the clinical outcome of 90YIT. The J3Zi study is composed of data from patients receiving 90YIT for rr-B-NHL from the top three institutions with 10 years of 90YIT treatment experience from October 2008 to May 2018 in Japan. The efficacy, prognostic factors and safety of 90YIT were retrospectively evaluated. Data from 316 patients were analyzed; the mean age was 64.6 years and the median number of prior treatments was 2. The median PFS was 3.0 years, the final OS rate was over 60%, and the median OS was not reached during the study period. Significant factors influencing PFS were sIL-2R ≤ 500 (U/mL) and no disease progression within 24 months of first treatment. Significant factors influencing OS were number of prior treatments ≤ 2 and sIL-2R ≤ 500 (U/mL). The PFS and OS rates were found to be significantly higher in the late half era (2013 to 2018) than in the early half era (2008 to 2013) during the study period. Prognosis following 90YIT treatment was improved in the late half era compared to the early half era. As treatment using 90YIT increased, administration of 90YIT shifted to the earlier treatment line. This may have contributed to the improvement of prognosis found in the late era. (UMIN000037105).

Evaluating the Emulsifying Capacity of Cellulose Nanofibers Using Inverse Gas Chromatography.

Cellulose nanofibers (CNFs) are attracting increasing attention as emulsifiers owing to their high emulsifying capacity, biocompatibility, and biodegradability. The emulsifying capacity has been experimentally shown to depend not only on the type of oil but also on the chemical structure of the CNF surface. However, the theoretical relationship between these two factors and emulsification remains unclear, and therefore, industrial applications are limited. Here, we assess the desorption energy (DE) of CNFs from the oil surface in o/w emulsion for various CNF/oil combinations to understand the mechanism of emulsification. Two types of surface-carboxylated CNFs having different cationic counterions, namely, sodium and tetrabutylammonium ions, were used as emulsifiers. The surface free energies of the CNFs were evaluated using inverse gas chromatography, and the nonpolar Lifshitz-van der Waals γLW, electron-acceptor γ+, and electron-donor γ- components were obtained from the chromatography profiles based on the van Oss-Chaudhury-Good theory. CNF with tetrabutylammonium ions was found to have a higher γ+ component than CNF with sodium ions. Therefore, the emulsion stability improved with oils having high γ- components owing to the increase in the DE value; this was verified through both theoretical calculations using a fibrous model and experimental dynamic interfacial tension measurements. Our approach is useful for predicting the emulsifying capacity of CNFs, and it should contribute toward the design of novel CNF-based emulsions.

Alectinib in a patient with ALK-positive non-small lung cancer unable to swallow capsules.

INTRODUCTION: The treatment landscape of metastatic non-small-cell lung cancer (NSCLC) has changed dramatically in the last decade. Anaplastic lymphoma kinase (ALK) rearrangement has been a focus of interest since ALK inhibitors produced outstanding clinical results compared with chemotherapy with cytotoxic agents in patients with ALK-positive NSCLC. CASE REPORT: We present the case of a 56-year-old woman with metastatic ALK-positive NSCLC and an inability to swallow capsules or tablets. Unfortunately, all ALK inhibitors are capsule or tablet formulations. MANAGEMENT AND OUTCOME: We, therefore, decided to administer alectinib orally by opening the capsules and suspending the contents in water. Clinical imaging performed 12 months after initiating alectinib therapy indicated a complete response (CR). After 54 months of follow-up, CR has been maintained, and oral alectinib therapy has continued with no recurrence of the swallowing disturbance. DISCUSSION: There are no current guidelines for oral targeted therapy in patients with swallowing disturbance, but alectinib administered orally by opening the capsules and suspending the contents in water can be a treatment option in patients with ALK-positive NSCLC and swallowing difficulty.

Decreased Proteasomal Function Induces Neuronal Loss and Memory Impairment.

Alzheimer disease (AD) is a progressive neurodegenerative disorder and the most common type of dementia worldwide. There is considerable evidence of age-related disruption of proteostasis being responsible for the development of AD. The proteasome is a multicatalytic enzyme complex that degrades both normal and damaged proteins, and an age-related decline in its activity has been implicated in age-related pathologies. Although proteasomal dysfunction is assumed to be a key AD hallmark, it remains unclear whether its role in disease onset is causative or secondary. In this study, we demonstrate that mice with proteasomal dysfunction exhibited memory impairment with associated neuronal loss, accumulation of phosphorylated tau, and activation of endoplasmic reticulum (ER) stress-related apoptosis pathways. Impaired proteasomal activity also activated ER stress-related apoptosis pathways in HT-22, a murine hippocampal neuronal cell line. HT-22 cell death, caused by proteasomal inhibition, was prevented by an inhibitor of c-Jun N-terminal kinase, an ER stress-related molecule. Collective evidence suggests that impaired proteasomal activity alters proteostasis, and subsequent ER stress-mediated pathways play pivotal roles in neuronal loss. Because aging decreases proteasomal function, age-related impairment of proteasomes may be involved in the development and progression of AD in elderly patients.

Healthcare resource utilization trends in patients with acute myeloid leukemia ineligible for intensive chemotherapy receiving first-line systemic treatment or best supportive care: A multicenter international study.

OBJECTIVES: This retrospective chart review examined real-world healthcare resource utilization (HRU) in patients with AML ineligible for intensive therapy who received first-line systemic therapy or best supportive care (BSC). METHODS: Data were collected anonymously on patients with AML who initiated first-line hypomethylating agents (HMA), low-dose cytarabine (LDAC), other systemic therapy, or BSC. HRU endpoints included hospitalizations, outpatient consultations, transfusions, and supportive care. RESULTS: Of 1762 patients included, 46% received HMA, 11% received LDAC, 17% received other systemic therapy, 26% received BSC; median treatment durations were 118, 35, 33, and 57 days, respectively. Most patients were hospitalized, most commonly for treatment administration, transfusion, or infection (HMA 82%, LDAC 93%, other systemic therapy 83%, BSC 83%). A median number of hospitalizations were 2-6 across systemic groups and two for BSC, with median durations of 8-18 days. Transfusion rates and outpatient consultations were highest for HMA (80% and 79%) versus LDAC (57% and 53%), other systemic therapy (57% and 63%), and BSC (71% and 66%). Antivirals/antibiotics and antifungals were used more frequently than growth factors (72-92%, 34-63%, and 7-27%, respectively). CONCLUSION: Patients with AML ineligible for intensive therapy have high HRU; novel therapies are needed to alleviate this burden.

Real-world efficacy of letermovir prophylaxis for cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation: A single-center retrospective analysis.

INTRODUCTION: Cytomegalovirus (CMV) infection is a common complication following allogeneic hematopoietic stem cell transplantation (aHSCT) and is associated with increased mortality. Letermovir (LET) is a novel antiviral drug used to prevent CMV infection. METHODS: We analyzed 111 consecutive patients who underwent aHSCT, retrospectively, to evaluate the efficacy of LET prophylaxis for clinically significant CMV infection (csCMVi) in real-world situations. In addition, we analyzed the influence of LET on transplant outcomes. Thirty-eight patients who were administered LET prophylactically were compared with 73 patients without LET prophylaxis after aHSCT. RESULTS: On day 180, the cumulative incidence of csCMVi in patients who received LET prophylaxis was significantly lower than that in patients without LET prophylaxis (29.7% vs. 56.2%, P < 0.001). Among the patients who developed csCMVi, the interval from aHSCT to the initiation of preemptive therapy was significantly longer in patients who received LET prophylaxis than in those who did not (129.5 days vs. 42 days, P < 0.001). The six-month overall survival was 86.1% in patients who received LET prophylaxis and 66.8% in the non-LET group (P = 0.035). CONCLUSION: LET prophylaxis was highly effective in preventing csCMVi and could potentially improve transplant outcomes, particularly when initiated early after transplantations.

Plateau is a prognostic factor of lenalidomide therapy for previously treated multiple myeloma.

The plateau phase emerging during the treatment of multiple myeloma (MM) is known to last steadily for a certain period, even without treatment. Therefore, the treatment started at plateau phase is expected to be associated with a better outcome. In this study, this hypothesis was evaluated retrospectively for previously treated MM patients in Kansai Myeloma Forum database who received lenalidomide (LEN) with or without dexamethasone for the first time. Disease stability index (DSI) was defined as (maximum - minimum values of M protein during the 90 days before the start of LEN) divided by M-protein values at the start of LEN. The patients were classified into three groups: stable (S), DSI ≤ 0.25; increasing (I), DSI > 0.25 with increasing M protein; decreasing (D), DSI > 0.25 with decreasing M protein. In univariate analysis of 352 patients, DSI group "I", non-IgG type, serum albumin<3.5 g/dL, and age≥70 were statistically significant prognostic factors for both progression-free survival and overall survival. In multivariate analysis, the former 3 risk factors were statistically significant for poor overall survival. Thus, DSI is an independent prognostic factor for the treatment with LEN for previously treated MM.

GM-CSF therapy inhibits chronic graft-versus-host disease via expansion of regulatory T cells.

Regulatory T cells (Tregs) attenuate excessive immune responses, making their expansion beneficial in immune-mediated diseases, including allogeneic bone marrow transplantation associated with graft-versus-host disease (GVHD). In addition to interleukin-2, Tregs require T-cell receptor and costimulatory signals from antigen-presenting cells, such as DCs, for their optimal proliferation. Granulocyte-macrophage colony-stimulating factor (GM-CSF) increases DC number and may promote DC-dependent Treg proliferation. Here, we demonstrate that GM-CSF treatment increases CD4+ CD8- DCs, which are associated with Treg expansion. In a mouse model of chronic GVHD (cGVHD), GM-CSF therapy expanded Tregs, protected against the development of skin GVHD, and regulated both Th1 and Th17 responses in the peripheral lymph nodes, resulting in an attenuation of skin cGVHD. Notably, the expanded Tregs were instrumental to GM-CSF-mediated cGVHD inhibition, which was dependent upon an increased ratio of Tregs to conventional T cells rather than augmentation of suppressive function. These data suggest that GM-CSF induces Treg proliferation by expanding CD4+ CD8- DCs, which in turn regulate alloimmune responses in a cGVHD mouse model. Thus, GM-CSF could be used as a therapeutic DC modulator to induce Treg expansion and to inhibit excessive alloimmune responses in immune-related diseases.

Statins can suppress DC-mediated Th2 responses through the repression of OX40-ligand and CCL17 expression.

DCs and epithelial cell-derived thymic stromal lymphopoietin (TSLP) have pivotal roles in allergic inflammation. TSLP stimulates myeloid DCs to express OX40-ligand (OX40L) and CCL17, which trigger and maintain Th2 cell responses. We have previously shown that statins, which are HMG-CoA reductase inhibitors, have the ability to suppress type I IFN production by plasmacytoid DCs. Here, we extended our previous work to examine the immunomodulatory effect of statins on allergic responses, particularly the TSLP-dependent Th2 pathway induced by myeloid DCs. We found that treatment of TSLP-stimulated DCs with either pitavastatin or simvastatin suppressed both the DC-mediated inflammatory Th2 cell differentiation and CRTH2+ CD4+ memory Th2 cell expansion and also repressed the expressions of OX40L and CCL17 by DCs. These inhibitory effects of statins were mimicked by treatment with either a geranylgeranyl-transferase inhibitor or Rho-kinase inhibitor and were counteracted by the addition of mevalonate, suggesting that statins induce geranylgeranylated Rho inactivation through a mevalonate-dependent pathway. We also found that statins inhibited the expressions of phosphorylated STA6 and NF-κB-p50 in TSLP-stimulated DCs. This study identified a specific ability of statins to control DC-mediated Th2 responses, suggesting their therapeutic potential for treating allergic diseases.

Clinical efficacy of mogamulizumab for relapsed/refractory aggressive adult T-cell leukemia/lymphoma: A retrospective analysis.

OBJECTIVES: Although phase 2 studies have confirmed the efficacy of mogamulizumab for adult T-cell leukemia/lymphoma (ATL), real-world data on its benefits are limited. We assessed the benefits of mogamulizumab for relapsed/refractory ATL in clinical practice. METHODS: We retrospectively analyzed patients with acute- and lymphoma-type ATL. Among 57 patients diagnosed with ATL between January 2008 and August 2018, 42 who received salvage therapy were eligible, including 24 who received mogamulizumab. RESULTS: The overall response rate to mogamulizumab was 54.2%. Median survival time (MST) and 1-year overall survival (OS) rate from mogamulizumab initiation were 7.7 months and 42.0%, respectively. Patients with acute-type ATL showed longer MST (15.1 months) and higher 1-year OS (63.6%). MST without skin rash was 5.0 months, and 1-year OS was 34.3%; however, MST with skin rash was not reached and 1-year OS was 66.7%. Among patients who received the salvage therapy, longer MST and higher 1-year OS were observed with mogamulizumab than without mogamulizumab (P = .078; 9.2 vs. 3.9 months; 47.9% vs. 17.6%, respectively). Mogamulizumab administration improved prognosis in patients with acute-type ATL and skin rash. CONCLUSIONS: In clinical practice, mogamulizumab improved OS in patients with relapsed/refractory ATL, especially those with acute-type ATL and skin rash.

Efficacy and safety of anagrelide as a first-line drug in cytoreductive treatment-naïve essential thrombocythemia patients in a real-world setting.

OBJECTIVE: This study aimed to retrospectively assess the efficacy and safety of anagrelide in cytoreduction therapy-naïve essential thrombocythemia (ET) patients in a real-world setting. METHOD: Data from 53 ET patients who received anagrelide as a first-line therapy were reviewed for patient characteristics, antiplatelet status, cytoreduction status, therapeutic effects, adverse events, thrombohemorrhagic event development, progression to myelofibrosis or acute leukemia, and cause of death. RESULTS: The rate of achieving a platelet count of <600 × 109 /L during anagrelide monotherapy was 83.0%. Adverse events occurred in 32 of 53 patients, and tended to be slightly more severe in patients with cardiac failure; however, they were mostly tolerable. The therapeutic effect of anagrelide was consistent, regardless of genetic mutation profiles. The incidence of anemia as an adverse event was significantly higher in the CALR mutation-positive group. Favorable platelet counts were also achieved in patients for whom hydroxyurea was introduced as a replacement for anagrelide or in addition to anagrelide because of unresponsiveness or intolerance to treatment. CONCLUSION: In Japanese cytoreduction therapy-naïve ET patients, anagrelide administration as a first-line therapy demonstrated favorable effects in reducing platelet counts, and its safety profile that was generally consistent with those in previous reports.

[Successful treatment with brentuximab vedotin maintenance therapy after autologous stem cell transplantation in high-risk Hodgkin lymphoma].

A 56-year-old woman was diagnosed with classical Hodgkin lymphoma in December 2012. She achieved complete remission (CR) with six cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD). In March 2015, she experienced a relapse marked by high fever, respiratory discomfort, and pain in the left thigh owing to tumor involvement of the femur. She was treated with one cycle of brentuximab vedotin (BV), followed by irradiation of the left femoral lesion. She achieved partial remission (PR) but developed recurrence after the third cycle of BV. She achieved PR again with two cycles of standard bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimen; therefore, autologous stem cell transplantation (ASCT) was performed. Because the dosing interval used for BV therapy was longer than that in the recommended schedule, we could not definitively attribute her recurrence to BV resistance. Moreover, she maintained a good performance status after recurrence during subsequent cycles of BV therapy. Because of attaining PR after ASCT, she subsequently received a total of 12 BV cycles for consolidation. She achieved CR 3 months after ASCT and has remained in CR until 29 months. For patients who show relapse after initial BV therapy, retreatment with BV should be carefully considered. Patients who show relapse after achieving at least PR with initial BV therapy are potential candidates for post-ASCT BV maintenance therapy to reduce their tumor burden.

[Present Status and Problems of Management and Guidance for Visiting Pharmacy Service to In-home Patients by Hospital Pharmacists].

We conducted a survey of the background of 41 patients who received management and guidance from an in-home visiting pharmacy service and of the contents of support by the pharmacist, using patients' medical records from May 2016 to March 2017. Support comprised delivery of medicine to alleviate a burden to caregiver, suggesting medication, adjusting remaining medicines, and providing support during hospitalization. Out of 285 visits, there were 32 visits for which a medical fee could not be claimed. The main reasons for this were delivery of medicine on the day of visiting medical care, management of prescribed medicine at home, and delivery of temporal medicines. We used SWOT analysis to examine the problems and to consider improvements. The results showed that the different method for calculating medical fees is disadvantage for the hospital pharmacy, compared with the health insurance pharmacy. On the other hand, an advantage for the hospital pharmacist is that he or she can refer to the patient's medical records and support them during hospitalization.

Guanosine and its modified derivatives are endogenous ligands for TLR7.

Toll-like receptor (TLR) 7and 8 were considered to recognize single-strand RNA (ssRNA) from viruses. Although these receptors also respond to synthetic small chemical ligands, such as CL075 and R848, it remains to be determined whether these receptors sense natural small molecules or not. In the structure of human TLR8 (huTLR8) with ssRNA, there are two ligand-binding sites: one binds a uridine and the other binds an oligoribonucleotide (ORN). This finding demonstrates that huTLR8 recognizes degradation products of ssRNA, suggesting the presence of natural small ligands. We here show that TLR7 works as the sensor for guanosine (G)/2'-deoxyguanosine (dG) in the presence of ORN where ORN strengthens TLR7 interaction with G/dG. In addition, modified nucleosides such as 7-methylguanosine, 8-hydroxyguanosine (8-OHG) and 8-hydroxydeoxyguanosine (8-OHdG) activated TLR7 with ORNs. Importantly, 8-OHdG-a well-known oxidative DNA damage marker with unknown function-induced strong cytokine production comparable to G and dG both in mouse and human immune cells. Although 8-OHdG bound TLR7/ORN with lower affinity than dG did in isothermal titration calorimetry, administered 8-OHdG was metabolically more stable than dG in the serum, indicating that 8-OHdG acts on TLR7 as an endogenous ligand in vivo To address a role of G analogs in the disease state, we also examined macrophages from Unc93b1 (D34A/D34A) mice, which suffer from TLR7-dependent systemic inflammation, and found that Unc93b1 (D34A/D34A) macrophages showed significantly enhanced response to G alone or 8-OHdG with ORN. In conclusion, our results provide evidence that G, dG, 8-OHG and 8-OHdG are novel endogenous ligands for TLR7.