Long-Term Effect of Denosumab on Bone Disease in Patients with CKD.

BACKGROUND: The effect of long-term denosumab therapy and of denosumab discontinuation on the cortical bone of the hip regions in dialysis patients has not been studied. METHODS: This retrospective study investigated the cortical and trabecular compartments and estimated strength indices of the hip region, obtained using 3D-SHAPER software, after a maximum of 5 years of denosumab therapy in 124 dialysis patients. A Wilcoxon signed-rank test was used to identify the differences in each parameter before and after denosumab initiation. Similarly, we investigated the changes in these parameters after denosumab discontinuation in 11 dialysis patients. RESULTS: Integral and trabecular volumetric bone mineral densities (BMD) were significantly lower at the start of denosumab therapy than those in 1 year before denosumab initiation. After starting denosumab, areal BMD (median change +7.7% [interquartile range (IQR), +4.6 to +10.6]), cortical volumetric BMD (median change +3.4% [IQR, +1.0 to +4.7]), cortical surface BMD (median change +7.1% [IQR, +3.4 to +9.4]), and cortical thickness (median change +3.2% [IQR, +1.8 to +4.9]) showed a significantly higher trend for 3.5 years, which then stabilized at a higher value compared with baseline. A similar trend in the trabecular volumetric BMD (median change +9.8% [IQR, +3.8 to +15.7]) was observed over 2.5 years, with a higher value maintained thereafter. The whole area of the hip region improved after denosumab therapy. Similar trajectories were also found in the estimated strength indices. Conversely, at 1 year after denosumab discontinuation, these 3D parameters and estimated strength indices tended to largely worsen. The lateral aspect of the greater trochanter was the most pronounced location showing volumetric BMD loss. CONCLUSIONS: The BMD of both cortical and trabecular components in the hip region was significantly higher after starting denosumab therapy. However, these measurements exhibited a trend of declining substantially after the discontinuation of denosumab.

[A Case of Synchronous Solitary Splenic Metastasis of Sigmoid Colon Cancer Treated with Laparoscopic Resection].

An 82-year-old woman presented to our hospital with chief complaints of lower abdominal pain and nausea. Contrast- enhanced CT showed ileus of sigmoid colon cancer and a solitary splenic tumor. A metallic stent was placed for the primary lesion. FDG-PET showed high FDG accumulation in the solitary splenic tumor, and synchronous solitary splenic metastasis was diagnosed. Laparoscopic sigmoid colectomy and laparoscopic splenectomy were performed without changing the intraoperative position or port arrangement. Postoperative progress was favorable. The patient was discharged 9 days after surgery, and no sign of recurrence has been observed to date, at 4 months after surgery. Solitary splenic metastasis of colorectal cancer is extremely rare. This is the first case report of synchronous solitary splenic metastasis of colorectal cancer treated with laparoscopic resection in Japan. This procedure is considered effective and minimally invasive. We review and discuss the Japanese literature on this rare disease.

Potential benefit of the cathepsin S inhibitor, ASP1617, as a treatment for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the dysregulation of various cell types and immunological pathways. Autoantibodies play an important role in its pathogenesis. The presence of autoantibodies suggests that self-antigen presentation through major histocompatibility complex (MHC) class II on antigen presenting cells is involved in the pathogenesis of autoimmune diseases, including SLE. Cathepsin S (CatS) is a key protease for antigen peptide loading onto lysosomal/endosomal MHC class II molecules through invariant chain degradation to promote antigen presentation. Inhibition of CatS is therefore expected to suppress antigen presentation via MHC class II, T and B cell activation, and antibody production from B cells. Here, we report the pharmacological profile of ASP1617, a novel CatS inhibitor. ASP1617 induced invariant chain accumulation and decreased the expression level of MHC class ΙΙ on the cell surface in both mouse and human B cells. Further, ASP1617 prevented DO11.10 mice T cell proliferation to ovalbumin antigen. We investigated the effects of ASP1617 and mycophenolate mofetil (MMF) on the development of lupus-like nephritis in NZB/W F1 mice, a widely used SLE mouse model. Oral administration of ASP1617 suppressed anti-dsDNA IgG, prevented progression of lupus-like glomerulonephritis, and significantly prevented proteinuria excretion. In contrast, MMF did not suppress anti-dsDNA IgG. Further, we found that plasma and/or urine CatS levels were increased in specimens from NZB/W F1 mice and several SLE patients. These results indicate that CatS may be an attractive therapeutic target for the treatment of SLE.

Illusory Oscillation of the Central Rotation Axis.

In this study, we report a novel visual illusion for rotational motion, in which the central rotation axis of a partially invisible (apparent) square is perceived as exhibiting oscillatory rotation. To investigate the cause of this illusion, we measured the central position of a static apparent shape using an adjustment method (Experiment 1) and manipulated the speed of the rotating apparent square to test whether the illusion could be cancelled out by counteracting rotation using a constant method (Experiment 2). The results revealed that the perceived central position of a static apparent shape was shifted toward the outside. The shifted position depended on the orientation of the stimulus, and its position was arranged as if it was moving in a circular trajectory. In addition, the cancellation technique using counteracting rotation was successful, and cancellation of faster rotation required a greater radius of counteracting rotation. These results indicated that the illusion is induced by an interaction between illusory shifts of the central position of the static shape and the summation of motion vectors or motion momentum (e.g., centrifugal force) derived from shape representation by perceptual completion.

Higher Serum C-reactive Protein Level Represents the Immunosuppressive Tumor Microenvironment in Patients With Clear Cell Renal Cell Carcinoma.

INTRODUCTION: C-reactive protein (CRP), a representative inflammatory marker, could serve as a biomarker in renal cell carcinoma because CRP is an important prognostic factor. However, its detailed mechanism remains unknown. This study showed that higher CRP levels correlated with the tumor immune microenvironment, which leads to a worse prognosis. These findings can help to clarify the underlying mechanisms between the presence of systemic inflammatory reaction and prognosis. The aim of this study is to investigate the association between tumor immune microenvironment and CRP in patients with renal cell carcinoma (RCC) to explore the underlying mechanisms between CRP level and prognosis. PATIENTS AND METHODS: Immunohistochemical measurement of CD4, CD8, CD163 (M2 macrophages), and Foxp3 (Regulatory T [Treg] cells) was performed in patients with clear-cell RCC (n = 111) treated with radical or partial nephrectomy at our institution. The association between immunohistochemical status and preoperative serum CRP level and cancer-specific survival (CSS) was analyzed. RESULTS: Thirty-three patients (30%) had a high CRP level (≥ 5.0 mg/L), and the CSS rate was significantly worse among these patients than among the remaining patients (P < .001). In patients with strong infiltration of CD8+, Foxp3+, or CD163+ cells, CRP levels were significantly higher (P = .041, P = .001, and P = .035, respectively), and CSS was significantly worse compared with patients with weak infiltration (P = .040, P = .026, and P < .001, respectively). In multivariate analysis, strong CD163+ cells infiltration (P = .001) as well as pathologic T3 (P = .036), lymph-node involvement (P = .007), distant metastasis (P < .001), and Fuhrman nuclear grade 4 (P = .003) were independent prognostic factors for CSS. CONCLUSIONS: Infiltration of the immunosuppressive cells known as Tregs and M2 macrophages in the tumor microenvironment is associated with higher CRP and poor prognosis in patients with clear-cell RCC. CRP could reflect an immunosuppressive microenvironment.

Effective suppression of donor specific antibody production by Cathepsin S inhibitors in a mouse transplantation model.

Donor-specific antibodies (DSA) are a major risk factor for antibody-mediated rejection (ABMR) in solid organ transplantation, and ABMR remains a medical challenge. Therefore, effective anti-ABMR therapies are needed to improve overall graft survival. Cathepsin S (Cat S) is an essential protease for antigen peptide loading onto lysosomal/endosomal major histocompatibility complex (MHC) class II molecules to promote antigen presentation. Cat S deficiency produces immuno-deficient phenotypes including a suppressed humoral immune response, and Cat S inhibition reportedly prevents autoimmunity. However, little is known about the effects of Cat S inhibitors on organ transplantation, especially ABMR. Here, we report the pharmacological profile of novel Cat S inhibitors, AS2761325 and AS2863995, and explore their preventive potential on DSA production and acute rejection in a mouse cardiac transplantation model. Cat S inhibitors potently inhibited upregulation of antigen peptide loading MHC class II expression on the surface of splenic B cells and suppressed ovalbumin-induced T cell-dependent antibody production in mice. In a mouse cardiac transplantation model, oral administration of AS2761325 monotherapy inhibited DSA production without affecting graft survival. When combined with a suboptimal dose of tacrolimus, AS2761325 significantly prolonged graft survival. The more potent Cat S inhibitor AS2863995 also prolonged graft survival and almost completely suppressed DSA production. These results suggest that Cat S inhibitors may be promising ABMR prophylaxis drug candidates. Combination therapy comprising a Cat S inhibitor and calcineurin inhibitors may be a more effective immunosuppressive maintenance therapy for controlling both cell-mediated and antibody-mediated rejection.

Detection of Second Primary Malignancies of the Esophagus and Hypophraynx in Oral Squamous Cell Carcinoma Patients.

OBJECTIVE: To assess the usefulness of modified esophagogastroduodenoscopy (EGD) for the detection of second primary malignancies of the esophagus or hypopharynx in patients with oral squamous cell carcinoma and determine the association between the oral lesion subsite and esophageal or hypopharyngeal lesion occurrence. STUDY DESIGN: Retrospective review. METHODS: In total, 166 patients with oral squamous cell carcinoma without any established symptoms of esophageal or hypopharyngeal squamous cell carcinoma underwent modified EGD based on the Valsalva maneuver and U-turn method, image-enhanced endoscopy, and chromoendoscopy using Lugol's iodine for diagnosis. All suspected lesions were biopsied to determine the clinical stages and duplication rates. Odds ratios for the occurrence of duplicate lesions according to the oral lesion subsite were determined. RESULTS: In total, 37 esophageal and 16 hypopharyngeal lesions were detected. According to the Union for International Cancer Control/American Joint Committee on Cancer classification (2009), 75.7% and 5.4% esophageal lesions were classified as stage IA and IB, respectively, and 50% and 18.8% hypopharyngeal lesions as stage II and stage I, respectively. Approximately 59.1% and 50% esophageal and hypopharyngeal lesions, respectively, were successfully treated by endoscopic resection. Oral lesions involving the floor of the mouth were more frequently accompanied by second primary malignancies of the esophagus or hypopharynx. CONCLUSIONS: Modified EGD is an effective noninvasive technique for early diagnosis and treatment of second primary malignancies of the esophagus and hypopharynx in patients with oral squamous cell carcinoma. In particular, patients with floor of the mouth lesions need close monitoring for hypopharyngeal and esophageal lesions. LEVEL OF EVIDENCE: 3b.

Discovery and structural characterization of peficitinib (ASP015K) as a novel and potent JAK inhibitor.

Janus kinases (JAKs) are considered promising targets for the treatment of autoimmune diseases including rheumatoid arthritis (RA) due to their important role in multiple cytokine receptor signaling pathways. Recently, several JAK inhibitors have been developed for the treatment of RA. Here, we describe the identification of the novel orally bioavailable JAK inhibitor 18, peficitinib (also known as ASP015K), which showed moderate selectivity for JAK3 over JAK1, JAK2, and TYK2 in enzyme assays. Chemical modification at the C4-position of lead compound 5 led to a large increase in JAK inhibitory activity and metabolic stability in liver microsomes. Furthermore, we determined the crystal structures of JAK1, JAK2, JAK3, and TYK2 in a complex with peficitinib, and revealed that the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold of peficitinib forms triple hydrogen bonds with the hinge region. Interestingly, the binding modes of peficitinib in the ATP-binding pockets differed among JAK1, JAK2, JAK3, and TYK2. WaterMap analysis of the crystal structures suggests that unfavorable water molecules are the likely reason for the difference in orientation of the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold to the hinge region among JAKs.

Impact of Immunohistochemistry-Based Subtypes in Muscle-Invasive Bladder Cancer on Response to Chemoradiation Therapy.

PURPOSE: A bladder-sparing strategy is a useful option for patients with muscle-invasive bladder cancer (MIBC), in which the response to chemoradiation therapy (CRT) is primarily important in achieving favorable oncologic outcomes. Our objective is to evaluate the impact of immunohistochemistry (IHC)-based subtyping in MIBC on prediction of CRT response. METHODS AND MATERIALS: Treatment protocol consisted of induction CRT followed by partial or radical cystectomy as consolidative surgery; 118 eligible patients with nonmetastatic MIBC were retrospectively analyzed. Of these patients, 92 eventually underwent partial or radical cystectomy after CRT. We applied the IHC-based subtyping model developed by Lund University, which classifies patients into urobasal (Uro), genomically unstable (GU), and squamous cell cancer-like (SCCL) subtypes. GU and SCCL cancers are supposed to be highly aggressive and to have worse prognoses than Uro. Correlations of subtypes with CRT response were analyzed clinically in all patients and pathologically in 92 cystectomized patients. The impact of each subtype on cancer-specific mortality (CSM) was also analyzed. RESULTS: Of all patients, 26 (22%), 61 (52%), and 31 (26%) were classified into Uro, GU, and SCCL subtypes, respectively. Clinical complete response (CR) was achieved in 42% of patients overall after CRT, with a significantly higher proportion in GU patients (52%) and SCCL patients (45%) than in Uro patients (15%; P < .001 and P = .01, respectively). On multivariate analysis, the GU/SCCL subtype was a significant predictor of clinical CR, as was absence of hydronephrosis or concomitant carcinoma in situ. Analyses for pathologic CR in the cystectomized patients revealed analogous findings. Five-year CSM of Uro, GU, and SCCL patients was 16%, 23%, and 28% overall, respectively, and 19%, 22%, and 23% in cystectomized patients, respectively, with no significant difference among the subtypes. CR status after CRT was significantly and independently correlated with low CSM in both clinical and pathologic evaluations. CONCLUSIONS: GU and SCCL cancers showed significantly more favorable CRT response than did Uro cancers. IHC-based subtyping may improve clinical decisions about the indication of CRT for MIBC patients.

The Effects of Inboard Shoulder Belt and Lap Belt Loadings on Chest Deflection.

Chest injuries occur frequently in frontal collisions. During impact, tension in the lap belt is transferred to the inboard shoulder belt, which compresses the lower ribs of the occupant. In this research, inboard shoulder belt and lap belt geometries and forces were investigated to reduce chest deflection. First, the inboard shoulder belt geometry was changed by the lap/shoulder belt (L/S) junction for the rear seat occupant in sled tests using Hybrid III finite element simulation, sled tests and THOR simulation. As the L/S junction was closer to the ASIS (anterior superior iliac spine), chest deflection of the Hybrid III was smaller. The L/S junction around the ilium has the potential to reduce chest deflection without significant increase of head excursion. For THOR, although the chest deflection reduction effect due to closer L/S junction to the ASIS was observed, chest deflection was still substantially large since the lap belt overrode the ASIS. Second, measures to hook the ASIS of the THOR by the lap belt were examined. Sled tests at 30 and 50 km/h were conducted with THOR in the rear seat, and it was demonstrated that the outboard lap belt and buckle pretensioners improved the lap belt and ASIS interaction, and were also useful in reducing the deflection at the inboard-side of the lower chest. Finally, the lap belt overlap with the ASIS was compared among 10 volunteers, Hybrid III, and THOR. Some volunteers had the ASIS located at the torso-thigh junction, and the lap belt did not overlap the ASIS sufficiently. However, although the ASIS location of THOR is also at the torso-thigh junction, the lap belt overlapped the ASIS because of the abdomen's and femur's shape. In the future, it will be necessary to consider that the outboard lap belt and buckle pretensioners are also effective for the ASIS restraint of all human car occupants.

Anatomical study of the left superior mediastinal lymphatics for tracheal branches of left recurrent laryngeal nerve-preserving mediastinoscope-assisted surgery in esophageal cancer.

PURPOSE: Curative treatment of esophageal cancer requires meticulous superior mediastinal lymphadenectomy, in addition to esophagectomy, because superior mediastinal lymph node metastases are common in esophageal cancer. When preserving the tracheal branches of the left recurrent laryngeal nerve (RLN), good anatomical understanding is required for confirmation of the positional relationships between the courses of lymphatic vessels, lymph node distribution, and the left RLN and its tracheal branches. We performed a detailed anatomical examination of these relationships. METHODS: Macroscopic anatomical observation and histological examination was performed on cadavers. In addition to hematoxylin and eosin staining, immunostaining using antipodoplanin antibody D2-40 (podoplanin) was performed to identify the lymphatic vessels. RESULTS: The tracheal branches of the left RLN were clearly observed, but no lymphatic vessels crossing the ventral or dorsal side of the branches were identified either macro-anatomically or histologically. CONCLUSION: No complex lymphatic network structure straddling the plane composed of tracheal branches of the left RLN was found in the left superior mediastinum. This suggests that dissection of the lymph nodes around the left RLN via the pneumomediastinum method using the left cervical approach may allow preservation of the tracheal branches of the left RLN by maintaining dissection accuracy.

Discovery of tricyclic dipyrrolopyridine derivatives as novel JAK inhibitors.

Janus kinases (JAKs) play a crucial role in cytokine mediated signal transduction. JAK inhibitors have emerged as effective immunomodulative agents for the prevention of transplant rejection. We previously reported that the tricyclic imidazo-pyrrolopyridinone 2 is a potent JAK inhibitor; however, it had poor oral absorption due to low membrane permeability. Here, we report the structural modification of compound 2 into the tricyclic dipyrrolopyridine 18a focusing on reduction of polar surface area (PSA), which exhibits potent in vitro activity, improved membrane permeability and good oral bioavailability. Compound 18a showed efficacy in rat heterotopic cardiac transplants model.

Application of low-vacuum scanning electron microscopy in cytopathology: To what extent can adenocarcinoma be morphologically distinguished from squamous cell carcinoma in lung cancer?

BACKGROUND: Anticancer drugs for targeted molecular therapies have been applied to the treatment of lung cancer. Since the effects of medicine for adenocarcinoma (ADC) or squamous cell carcinoma (SQCC) differ, the ability to discriminate these lesions is important. In the present study, we examined whether ADC and SQCC could be distinguished using low-vacuum scanning electron microscopy (LVSEM) to examine cytopathological specimens. METHODS: Thirty-seven cases of bronchoscopic samples were retrospectively examined using LVSEM on the surface structures of the cancer cells. RESULTS: Among the Pap-stained slides, 81.1% of the cases could be distinguished: 96.2% of the ADC cases were distinguishable, and 45.5% of the SQCC cases were distinguishable. Among the significant findings for ADC using LVSEM, a spherical shape (73.1%), long filaments (65.4%), dense filaments (80.8%), and depression (57.7%) were seen. Among the significant findings for SQCC as observed using LVSEM, however, a flat shape (81.8%), sparse filaments (72.7%), and non-filament (81.8%) were seen. The overall accuracy of diagnosis using LVSEM was 83.8%: 80.8% for ADC and 90.9% for SQCC. The accuracy of a combination of Papstained slides and LVSEM was 97.3%. CONCLUSIONS: The LVSEM method is useful as an ancillary examination for cytopathology after the classification of Pap-stained slides.

Case of Superficial Cancer Located at the Pharyngoesophageal Junction Which Was Dissected by Endoscopic Laryngopharyngeal Surgery Combined with Endoscopic Submucosal Dissection.

Aims. In order to determine the indications of transoral surgery for a tumor located at the pharyngoesophageal junction, the trumpet maneuver with transnasal endoscopy was used. Its efficacy is reported here. Material and Methods. An 88-year-old woman complaining of dysphagia, diagnosed with cervical esophageal cancer, and hoping to preserve her voice and swallowing function was admitted to our hospital. Conventional endoscopy showed that the tumor had invaded the hypopharynx. When inspecting the hypopharynx and the orifice of the esophagus, we asked the patient to blow hard and puff her cheeks with her mouth closed (trumpet maneuver). After the trumpet maneuver, the pharyngeal mucosa was stretched out. The pedicle of the tumor arose from the left-anterior wall of the pharyngoesophageal junction, so we decided to perform endoscopic resection. Result. Under general anesthesia, the curved laryngoscope made it possible to view the whole hypopharynx, including the apex of the piriform sinus and the orifice of the esophagus. The cervical esophageal cancer was pulled up to the hypopharynx. Under collaboration between a head and neck surgeon and an endoscopist, the tumor was resected en bloc by endoscopic laryngopharyngeal surgery combined with endoscopic submucosal dissection. Conclusion. Transnasal endoscopy using the trumpet maneuver is useful for a precise diagnosis of the pharyngoesophageal junction. Close collaboration between head and neck surgeons and endoscopists can provide good results in treating tumors of the pharyngoesophageal junction.

Frequency of Propionibacterium acnes Infection in Prostate Glands with Negative Biopsy Results Is an Independent Risk Factor for Prostate Cancer in Patients with Increased Serum PSA Titers.

BACKGROUND: Propionibacterium acnes has recently been implicated as a cause of chronic prostatitis and this commensal bacterium may be linked to prostate carcinogenesis. The occurrence of intracellular P. acnes infection in prostate glands and the higher frequency of P. acnes-positive glands in radical prostatectomy specimens from patients with prostate cancer (PCa) than in those from patients without PCa led us to examine whether the P. acnes-positive gland frequency can be used to assess the risk for PCa in patients whose first prostate biopsy, performed due to an increased prostate-specific antigen (PSA) titer, was negative. METHODS: We retrospectively collected the first and last prostate biopsy samples from 44 patients that were diagnosed PCa within 4 years after the first negative biopsy and from 36 control patients with no PCa found in repeated biopsy for at least 3 years after the first biopsy. We evaluated P. acnes-positive gland frequency and P. acnes-positive macrophage number using enzyme-immunohistochemistry with a P. acnes-specific monoclonal antibody (PAL antibody). RESULTS: The frequency of P. acnes-positive glands was higher in PCa samples than in control samples in both first biopsy samples and in combined first and last biopsy samples (P < 0.001). A frequency greater than the threshold (18.5 and 17.7, respectively) obtained by each receiver operating characteristic curve was an independent risk factor for PCa (P = 0.003 and 0.001, respectively) with odds ratios (14.8 and 13.9, respectively) higher than those of serum PSA titers of patients just before each biopsy (4.6 and 2.3, respectively). The number of P. acnes-positive macrophages did not differ significantly between PCa and control samples. CONCLUSIONS: These results suggested that the frequency of P. acnes-positive glands in the first negative prostate biopsy performed due to increased PSA titers can be supportive information for urologists in planning repeated biopsy or follow-up strategies.

Design, synthesis, and evaluation of 4,6-diaminonicotinamide derivatives as novel and potent immunomodulators targeting JAK3.

In organ transplantation, T cell-mediated immune responses play a key role in the rejection of allografts. Janus kinase 3 (JAK3) is specifically expressed in hematopoietic cells and associated with regulation of T cell development via interleukin-2 signaling pathway. Here, we designed novel 4,6-diaminonicotinamide derivatives as immunomodulators targeting JAK3 for prevention of transplant rejection. Our optimization of C4- and C6-substituents and docking calculations to JAK3 protein confirmed that the 4,6-diaminonicotinamide scaffold resulted in potent inhibition of JAK3. We also investigated avoidance of human ether-a-go-go related gene (hERG) inhibitory activity. Selected compound 28 in combination with tacrolimus prevented allograft rejection in a rat heterotopic cardiac transplantation model.

Perceptual shrinkage of a one-way motion path with high-speed motion.

Back-and-forth motion induces perceptual shrinkage of the motion path, but such shrinkage is hardly perceived for one-way motion. If the shrinkage is caused by temporal averaging of stimulus position around the endpoints, it should also be induced for one-way motion at higher motion speeds. In psychophysical experiments with a high-speed projector, we tested this conjecture for a one-way motion stimulus at various speeds (4-100 deg/s) along a straight path. Results showed that perceptual shrinkage of the motion path was robustly observed in higher-speed motion (faster than 66.7 deg/s). In addition, the amount of the forwards shift at the onset position was larger than that of the backwards shift at the offset position. These results demonstrate that high-speed motion can induce shrinkage, even for a one-way motion path. This can be explained by the view that perceptual position is represented by the integration of the temporal average of instantaneous position and the motion representation.

Transient twinkle perception is induced by sequential presentation of stimuli that flicker at frequencies above the critical fusion frequency.

The critical fusion frequency (CFF) is a threshold that represents the temporal limits of the human visual system. If two flickering stimuli with equal subjective luminances are presented simultaneously at different locations, the CFF is the temporal frequency above which they cannot be distinguished. However, when the stimuli are presented sequentially at the same position, a transient twinkle can be perceived around the moment of the changeover. To investigate the mechanism underlying this transient twinkle perception (TTP), we independently manipulated the luminance contrast and temporal frequency of the flicker, as well as the interstimulus interval (ISI). We found that TTP was greater as the luminance step was larger, was stably perceived for flicker frequencies up to 200 Hz, and was robust for all ISIs if flicker frequencies were below 250 Hz. For 250- and 300-Hz flickers, TTP was attenuated in conditions in which one-frame and two-frame ISIs were inserted. These results can be explained by a simple filtering model: TTP occurs if the temporal change in the weighted moving average of stimulus luminance exceeds a certain threshold. TTP gives additional evidence that the human visual system can detect the transient change of flicker stimuli at much higher temporal frequencies than the CFF, by an averaging mechanism of luminance.