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.

Changes in diagnostic usefulness of the JRS scoring system in COVID-19 pneumonia by SARS-CoV-2 vaccination.

INTRODUCTION: The Japanese Respiratory Society (JRS) scoring system is a useful tool for the rapid presumptive diagnosis of atypical pneumonia in non-elderly (aged <60 years) patients. As SARS-CoV-2 vaccination progresses, COVID-19 in elderly people has markedly reduced. We investigated changes in diagnostic usefulness of the JRS scoring system in COVID-19 pneumonia between the Delta variant group (vaccination period) and non-Delta variant group (before the vaccination period). METHODS: This study was conducted at five institutions and assessed a total of 1121 patients with COVID-19 pneumonia (298 had the Delta variant). During the vaccination period, the Delta variant has spread and replaced the Alfa variant. We evaluated the vaccination period as the Delta variant group. RESULTS: Among the six parameters of the JRS scoring system, matching rates of two parameters were higher in the Delta variant group than the non-Delta variant group (pre-vaccination period): age <60 years (77.5% vs 42.2%, P < 0.0001) and no or minor comorbid illness (69.1% vs 57.8%, p = 0.0007). The sensitivity of the diagnosis of atypical pneumonia in patients with COVID-19 pneumonia was significantly higher in the Delta variant group compared with the non-Delta variant group (80.2% vs 58.3%, p < 0.0001). When the diagnostic sensitivity was analyzed for different ages, the diagnostic sensitivities for the Delta variant and non-Delta variant groups were 92.6% and 95.5% for non-elderly patients and 39.1% and 32.5% for elderly patients, respectively. CONCLUSIONS: Our results demonstrated that the JRS scoring system is a useful tool for distinguishing between COVID-19 pneumonia and bacterial pneumonia in the COVID-19 vaccination period, but not before the vaccination period.

Early identification of novel coronavirus (COVID-19) pneumonia using clinical and radiographic findings.

INTRODUCTION: The Japanese Respiratory Society (JRS) scoring system is a useful tool for identifying Mycoplasma pneumoniae pneumonia. Most COVID-19 pneumonia in non-elderly patients (aged <60 years) are classified as atypical pneumonia using the JRS scoring system. We evaluated whether physicians could distinguish between COVID-19 pneumonia and M. pneumoniae pneumonia using chest computed tomography (CT) findings. In addition, we investigated chest CT findings if there is a difference between the variant and non-variant strain. METHODS: This study was conducted at five institutions and assessed a total of 823 patients with COVID-19 pneumonia (335 had lineage B.1.1.7.) and 100 patients with M. pneumoniae pneumonia. RESULTS: In COVID-19 pneumonia, at the first CT examination, peripheral, bilateral ground-glass opacity (GGO) with or without consolidation or crazy-paving pattern was observed frequently. GGO frequently had a round morphology (39.2%). No differences were observed in the radiological findings between the non-B.1.1.7 groups and B.1.1.7 groups. The frequency of pleural effusion, lymphadenopathy, bronchial wall thickening and nodules (tree-in-bud and centrilobular) was low. In contrast to COVID-19 pneumonia, bronchial wall thickening (84%) was observed most frequently, followed by nodules (81%) in M. pneumoniae pneumonia. These findings were significantly higher in M. pneumoniae pneumonia than COVID-19 pneumonia. CONCLUSIONS: Our results demonstrated that a combination of the JRS scoring system and chest CT findings is useful for the rapid presumptive diagnosis of COVID-19 pneumonia in patients aged <60 years. However, this clinical and radiographic diagnosis is not adapted to elderly people.

Clinical features of nursing and healthcare-associated pneumonia due to COVID-19.

INTRODUCTION: The objective of this study was to clarify the clinical differences between nursing and healthcare-associated pneumonia (NHCAP) and community-acquired pneumonia (CAP) due to COVID-19. We also investigated the clinical characteristics to determine whether there is a difference between the variant and non-variant strain in patients with NHCAP due to COVID-19. In addition, we analyzed the clinical outcomes in NHCAP patients with mental disorders who were hospitalized in a medical institution for treatment of mental illness. METHODS: This study was conducted at five institutions and assessed a total of 836 patients with COVID-19 pneumonia (154 cases were classified as NHCAP and 335 had lineage B.1.1.7.). RESULTS: No differences in patient background, clinical findings, disease severity, or outcomes were observed in patients with NHCAP between the non-B.1.1.7 group and B.1.1.7 group. The median age, frequency of comorbid illness, rates of intensive care unit stay, and mortality rate were significantly higher in patients with NHCAP than in those with CAP. Among the patients with NHCAP, the mortality rate was highest at 37.5% in patients with recent cancer treatment, followed by elderly or disabled patients receiving nursing care (24.3%), residents of care facilities (23.0%), patients receiving dialysis (13.6%), and patients in mental hospitals (9.4%). CONCLUSIONS: Our results demonstrated that there were many differences in the clinical characteristics between NHCAP patients and CAP patients due to COVID-19. It is necessary to consider the prevention and treatment content depending on the presence or absence of applicable criteria for NHCAP.

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.

Outcomes of ixazomib/lenalidomide/dexamethasone for multiple myeloma: A multicenter retrospective analysis.

OBJECTIVES: This study aimed to investigate real-world data of ixazomib plus lenalidomide and dexamethasone (IRd) therapy for patients with relapsed and refractory multiple myeloma (RRMM). METHODS: We retrospectively analyzed 122 patients treated with IRd at 16 centers from May 2017 to January 2019 by using the Kansai Myeloma Forum database. RESULT: At the start of IRd, the median age was 72 years, 66.7% of patients had IgG type, and the median number of prior therapies was 4, comprising bortezomib (85.4%) and lenalidomide (89.3%)-based regimens. Disease progression and adverse events accounted for treatment discontinuation in 46 and 32 patients, respectively. The median overall survival (OS) was not reached, and the median progression-free survival (PFS) was 11.9 months. Sensitivity to bortezomib did not affect the PFS, whereas lenalidomide-refractory patients had significantly lower PFS than lenalidomide-sensitive patients, who were comparable to TOURMALINE-MM1 study. The patients with IgG type had significantly better PFS and OS than those with non-IgG type. CONCLUSION: This study presents the largest real-world data of patients treated with IRd in Asia. However, in real clinical practice, the patient background is different from the TOURMALINE-MM1 study, and IRd showed poor efficacy, especially in the non-IgG type and lenalidomide-refractory patients with RRMM.

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.

IL-2-Anti-IL-2 Monoclonal Antibody Immune Complexes Inhibit Collagen-Induced Arthritis by Augmenting Regulatory T Cell Functions.

IL-2 induces regulatory T cells (Tregs) and reduces disease severity, such as in graft-versus-host disease and systemic lupus erythematosus. To investigate the regulatory network of IL-2 in rheumatoid arthritis, we examined the effects of IL-2-anti-IL-2 mAb immune complexes (IL-2ICs) in a rheumatoid arthritis model of collagen-induced arthritis (CIA). CIA was induced in male DBA/1 mice by two immunizations with type II collagen at 3-wk intervals. IL-2ICs were prepared by mixing 5 µg of an anti-IL-2 mAb (clone JES6-1D) with 1 µg of mouse IL-2 and were injected i.p. every day for 3 d. Mouse paws were scored for arthritis using a macroscopic scoring system. Th1, Th2, Th17, and Tregs were analyzed by flow cytometry. Joint histopathology was examined by H&E and immunohistochemical staining. Treg functions were examined by studying in vitro suppression using flow cytometry. IL-2IC administration effectively elicited a 1.6-fold expansion of CD4+Foxp3+ Tregs in peripheral blood cells relative to that found in control mice. IL-2IC treatment significantly inhibited arthritis in CIA mice. Histopathological examination of joints revealed inhibited synovial cell proliferation and IL-17, IL-6, and TNF-α levels but increased Foxp3+ Tregs after IL-2IC treatment. Flow cytometric examination of spleen cells revealed reduced IFN-γ- and IL-17-producing cells and increased IL-10-producing Tregs after IL-2IC treatment. The suppressive activities of CD4+CD25+ Tregs induced by IL-2ICs were stronger than those in untreated mice. IL-2ICs inhibited arthritis by augmenting not only Treg numbers but also Treg functions, which play regulatory roles in autoimmune arthritis.

Detection of Mycoplasma pneumoniae using a highly sensitive rapid diagnostic method with silver amplification technology.

To prevent an increase in the frequency of antimicrobial resistance (AMR), the specific and rapid diagnosis of causative pathogens is important, as the results can be used to initiate appropriate antibiotics treatment. Recently, the highly sensitive rapid immunochromatographic assay of silver amplification technology was developed for the detection of Mycoplasma pneumoniae. We investigated the sensitivity and specificity of the silver amplification immunochromatographic assay in adolescent and adult patients. A total of 767 patients with respiratory tract infection (RTI) and 605 with pneumonia were assessed by the silver amplification assay and real-time polymerase chain reaction (PCR). M. pneumoniae was identified by PCR in 95 patients with RTI and in 30 patients with community-acquired pneumonia (CAP), but it was not identified in patients with nursing- and healthcare-associated pneumonia. Eighteen of the 95 RTI patients and 7 of the 30 CAP patients with PCR-positive M. pneumoniae were found to be infected with macrolide-resistant M. pneumoniae. When PCR was used as the control test, the sensitivity, specificity, and overall agreement with the silver amplification assay were 90.5%, 99.0%, and 97.9%, respectively, in RTI patients and 90.0%, 99.1%, and 98.7%, respectively, in pneumonia patients. Our results show that the silver amplification assay has excellent sensitivity and specificity compared with PCR despite being a rapid diagnostic method. The silver amplification assay may be helpful for initiating appropriate antibiotic treatment and preventing AMR.

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.

Effect of triple therapy in patients with asthma-COPD overlap
.

OBJECTIVE: Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is of increasing interest because ACO patients have significantly worse outcomes, leading to greater social and economic burdens compared with asthma or COPD alone. Some guidelines for ACO recommend triple therapy with inhaled corticosteroids, long-acting ß2 agonists, and long-acting muscarinic antagonists. However, this approach is based on extrapolating data from patients with asthma or COPD alone. Therapeutic studies for ACO have not previously been conducted. MATERIALS AND METHODS: A 12-week, randomized, open-label cross-over pilot study was conducted in 17 ACO patients to evaluate the effect of umeclidinium (UMEC) 62.5 µg once-daily added to fluticasone furoate/vilanterol (FF/VI) 200/25 µg once-daily. A 4-week run-in, a first and a second 4-week treatment period were included. Respiratory function, respiratory impedance, fractional exhaled nitric oxide, COPD assessment test, and asthma control test scores were evaluated 0, 4, and 8 weeks after randomization. RESULTS: Mean values of post-bronchodilator forced expiratory volume in 1 second as a percentage of the predicted value (%FEV1), after UMEC was added to FF/VI, were significantly higher than after the run-in (p < 0.01). Mean values of resonant frequency during inspiration (Fres), after UMEC was added to FF/VI, were significantly lower than after the run-in (p < 0.01). CONCLUSION: Adding UMEC to FF/VI provides greater improvement in lung function, indicating that triple therapy is a suitable regular treatment for ACO.

Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with advanced non-small-cell lung cancer treated with nivolumab.

BACKGROUND: There is an unmet need to identify markers that predict the response to nivolumab in patients with non-small-cell lung cancer (NSCLC). The neutrophil-to-lymphocyte ratio (NLR) was recently recognized as an indicator of a poor prognosis in patients with various cancers. In the present study, we quantified the predictive impact of NLR in patients with NSCLC treated with nivolumab. METHODS: We retrospectively analyzed 101 patients with advanced NSCLC treated with nivolumab at Kansai Medical University Hospital from December 2015 to December 2016. Patients were administered nivolumab at a dose of 3 mg/kg every 2 weeks. The predictive value of NLR for disease progression before treatment and 2 and 4 weeks after nivolumab treatment was assessed. RESULTS: The median progression-free survival (PFS) of patients with an NLR of < 3 before treatment was 3.4 months, whereas that of patients with an NLR of ≥ 3 was 2.9 months (p = 0.484). The median PFS of patients with an NLR of < 3 at 2 weeks after treatment was 5.3 months, whereas that of patients with an NLR of ≥ 3 was 2.1 months (p = 0.00528). The median PFS of patients with an NLR of < 3 at 4 weeks after treatment was 5.3 months, whereas that of patients with an NLR of ≥ 3 was 2.0 months (p = 0.00515). CONCLUSION: The NLR at 2 and 4 weeks after treatment might be a useful marker for the prediction of the treatment response or disease progression in patients with advanced NSCLC receiving nivolumab.

[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.

[Effect of Japanese Traditional Medicine, Ninjin-Youei-To(TJ-108), on the Quality of Life of Patients with Non-Small Cell Lung Cancer Receiving Outpatient Chemotherapy].

An increasing number of patients with lung cancer are undergoing outpatient chemotherapy, and thus, it is very important to maintain the quality of life(QOL)of these patients. Ninjin-Youei-To(TJ-108), a Japanese traditional medicine, has been reported to improve the QOL of patients with advanced cancer. However, the effect of TJ-108 in patients with lung cancer undergoing outpatient chemotherapy is unknown. Therefore, we conducted this study. To investigate factors influencing the QOL of these patients, we administered a QOL questionnaire,"The QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs"(QOL-ACD)to 15 patients with non-small cell lung cancer. Factors related to the overall QOL scores and other categories indicating"activity","physical condition","psychological condition","social relationship", and"face scale" were analyzed. No significant decrease in each of the evaluated factors was observed in this study.

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.

Realistic Lenalidomide Dose Adjustment Strategy for Transplant-Ineligible Elderly Patients with Relapsed/Refractory Multiple Myeloma: Japanese Real-World Experience.

Lenalidomide is an immunomodulatory drug administered orally in the treatment of multiple myeloma. Some elderly patients require a reduced lenalidomide dose because of comorbidities and/or adverse events. This study investigated the actual dose of lenalidomide in elderly patients, finding that most received reduced (5-10 mg) doses. The most common reasons for dose reduction were renal dysfunction (54% of patients), fatigue (grade ≥3; 20%), hematologic disorder (grade ≥3; 14%), and rash (grade ≥3; 9%). Their median time to progression was 11.8 months and their median overall survival was 39.2 months. The overall response rate was 73%, including 17% with a complete response, 19% with a very good partial response, and 37% with a partial response. These results showed that, contrary to western countries, most patients were treated with a reduced dose of lenalidomide in Japan. However, it is suggested that continued treatment with a tolerable dose may yield favorable outcomes.