[A Case of Advanced Gastric Cancer Treated with Conversion Surgery followed by Nivolumab Combination Chemotherapy].

The use of nivolumab as first-line therapy for unresectable advanced gastric cancer has now become a standard practice, and its efficacy has been established. This is the first report of a patient with advanced gastric cancer who underwent conversion surgery after first-line nivolumab combination chemotherapy. The patient was a 58-year-old woman. Her medical history included hypertension and dyslipidemia. She had advanced gastric cancer with extensive lymph node metastasis in the left supraclavicular fossa and around the abdominal aorta. After confirming the HER2-negative status and the PD-L1 CPS score to be ≥5, nivolumab was administered in combination with chemotherapy. After the treatment, she underwent a total gastrectomy with D2 dissection, combined splenectomy and pancreatic tail resection for adhesions, and para-aortic lymph node sampling as a conversion surgery. There was no obvious cancerous remnant in the resected specimen, and the pathological response was Grade 3. The patient was alive and recurrence-free at 4 months postoperatively.

Assessing effects of mechanical stimulation of fluid shear stress on inducing matrix Metalloproteinase-9 in cultured corneal epithelial cells.

Blinking is regarded as mechanical stimulation of fluid shear stress on the corneal epithelial cells. Therefore, we evaluated whether fluid shear stress affects matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in cultured human corneal epithelial cells (HCECs). No other study has shown the influence of fluid shear stress on HCECs regarding mRNA expression and the protein levels of MMPs. Cultured HCECs were exposed to shear stress (0, 1.2, 12 dyne/cm2) for 12 and 24 h with the parallel-plate type of flow chamber. Gene expression of MMPs and TIMPs was measured by real-time polymerase reaction. Concentrations of MMP-1 and MMP-9 in cell lysates were determined using bead-based amplified luminescent proximity homogenous assay-linked immunosorbent assay. The expression of MMP-9 and MMP-1 in HCECs exposed to low and high flow for 12 and 24 h, respectively, increased significantly compared with those under static conditions. The expression of MMP-9 in the cells exposed to high flow for 24 h increased significantly compared with those under static and low flow conditions. Levels of MMP-9 in cell lysates exposed to fluid flow for 24 h were elevated significantly with increasing shear stress. Fluid shear stress exerted on HCECs affected MMPs, which was associated with inflammation and pathogenesis. Mechanical stress induced by blinking might influence expression of MMPs on the ocular surface. Further studies are warranted to establish the molecular mechanism of shear stress-induced alternations of MMPs.

Glaucoma Diagnostic Performance of Retinal Blood Flow Measurement With Doppler Optical Coherence Tomography.

Purpose: The purpose of this study was to evaluate the diagnostic performance of retinal blood flow (RBF) measured with the Doppler optical coherence tomography (OCT) segmental scanning method to distinguish between healthy and glaucoma eyes. Methods: Fifty-eight patients with normal tension glaucoma (NTG) who had a single-hemifield visual field defect and 44 age-matched healthy subjects were enrolled. Retinal nerve fiber layer thickness (RNFLT) was measured with swept-source OCT. Superior and inferior temporal arteries (TAs) and temporal veins (TVs) RBF were measured with Doppler OCT. The area under the curve (AUC) of the receiver operating characteristic (ROC) was used to compare the diagnostic performances in the damaged and normal hemispheres. Results: Multivariate regression analysis showed TA RBF and TV RBF were significantly reduced in the damaged and normal hemispheres. The ROC analysis showed that the AUC for quadrant RNFLT, TA RBF, and TV RBF were 0.973, 0.909, and 0.872 in the damaged hemisphere, respectively. The AUC values in the normal hemisphere were 0.783, 0.744, and 0.697, respectively. The combination of quadrant RNFLT and TA/TV RBF had a greater AUC than quadrant RNFLT alone in both damaged (AUC = 0.987) and normal (AUC = 0.825) hemispheres. Conclusions: In NTG eyes with single-hemifield damage, the RBF was found to be significantly reduced in the damaged and normal hemispheres independent from structural changes. The combination of RNFLT and RBF could improve diagnostic performances for glaucoma. Translational Relevance: Combining morphological and blood flow measurements with Doppler OCT may be useful in glaucoma diagnosis.

Retinal Blood Velocity Waveform Characteristics With Aging and Arterial Stiffening in Hypertensive and Normotensive Subjects.

Purpose: We aimed to explore the velocity waveform characteristics of the retinal artery associated with age and the cardio-ankle vascular index (CAVI) as a conventional arterial stiffness marker by applying the Doppler optical coherence tomography (DOCT) flowmeter. Methods: In this cross-sectional study, DOCT flowmeter imaging was performed in 66 participants aged 21 to 83 years (17 men, 49 women) with no history of eye diseases and no systemic diseases, except for hypertension. Retinal blood velocity waveform was analyzed where several parameters in time (upstroke time, T1, T2, T3, and T4) and area under the waveform (area elevation, area declination, A1, A2, A3, and A4) were extracted. Systolic blood pressure-adjusted Pearson's coefficients were calculated to determine the correlations of each parameter with age or CAVI. Results: Corrected upstroke time (UTc) was the waveform parameter most positively correlated with age (r = 0.497, P < 0.001). Area declination was the waveform parameter most negatively correlated with age (r = -0.682, P < 0.001) and CAVI (r = -0.601, P < 0.001). Conclusions: We extracted the waveform parameters associated with the risks of arterial stiffening. The velocity waveform analysis of the retinal artery with DOCT flowmeter potentially could become a new method for arterial stiffness identification. Translational Relevance: DOCT flowmeter could evaluate arterial stiffening in a different way from the conventional method of measuring arterial stiffening using pressure waveform. Because the DOCT flowmeter can easily, quickly, and noninvasively provide a retinal blood velocity waveform, this system could be useful as a routine medical examination for arterial stiffening.

Effect of insulin treatment on pulsatility ratio and resistance index of the retinal artery in patients with type 2 diabetes.

This study aimed to evaluate whether long-term insulin treatment is associated with abnormalities in retinal circulation in type 2 diabetic patients. We evaluated 19 eyes of nondiabetic individuals and 68 eyes of type 2 diabetic patients. The eyes of diabetic patients were classified into two groups according to the presence or absence of long-term insulin therapy. We used a Doppler optical coherence tomography flowmeter to measure diameter, velocity, and blood flow in the major temporal retinal artery. The pulsatility ratio (PR) and resistance index (RI), indices of vascular rigidity, were calculated from the blood velocity profile. PR and RI were significantly elevated in type 2 diabetic patients compared with nondiabetic subjects (P < 0.05). In type 2 diabetes patients, PR and RI were significantly higher in patients receiving long-term insulin treatment than in those without (P < 0.01). There was a significant difference in velocity (P < 0.05), but not diameter and blood flow, between nondiabetic subjects and type 2 diabetes patients. No significant difference in diameter, velocity, or blood flow was observed between the groups with and without long-term insulin treatment. Long-term insulin treatment can affect PR and RI, which might be associated with vascular rigidity of the retinal artery in patients with type 2 diabetes.

Retinal blood flow reduction in normal-tension glaucoma with single-hemifield damage by Doppler optical coherence tomography.

AIMS: To evaluate the associations between retinal blood flow (RBF) and optical coherence tomography (OCT) structural measurements in normal-tension glaucoma (NTG) eyes with single-hemifield visual field (VF) damage by the Doppler OCT. METHODS: The Doppler OCT was used to measure temporal artery (TA) RBF and temporal vein (TV) RBF. Retinal nerve fibre layer thickness (RNFLT) was measured by spectral-domain OCT. RESULTS: Forty-three consecutive eyes of 43 patients with NTG with VF defect confined to a single hemifield and 24 eyes of 24 age-matched healthy subjects were studied. TA and TV RBF and RNFLT were reduced in the damaged hemisphere compared with the normal hemisphere (mean (SD), 3.61 (1.68) vs 5.86 (2.59) µL/min, p<0.001; 5.61 (2.51) vs 6.94 (2.83) µL/min, p=0.010; 69.0 (19.7) vs 99.7 (22.8) µm, p<0.001). Those values in the normal hemisphere of NTG eyes also decreased compared with the healthy hemisphere of the healthy eyes (8.40 (3.36) µL/min, p<0.001; 9.28 (4.47) µL/min, p<0.002; 122.8 (20.2) µm, p<0.001). Multivariate model showed that normal and damaged hemispheres and RNFLT were associated with RBF reduction. In addition, the RBF in the normal hemisphere was lower than that in the healthy hemisphere even after adjusting for RNFLT. CONCLUSION: In NTG eyes with single-hemifield damage, the RBF was significantly reduced in the damaged hemisphere compared with the normal one. The RBF decreased in the normal and damaged hemispheres of NTG eyes compared with the healthy hemisphere independent from RNFLT.

Deterioration of Retinal Blood Flow Parameters in Branch Retinal Vein Occlusion Measured by Doppler Optical Coherence Tomography Flowmeter.

BACKGROUND: Doppler optical coherence tomography (DOCT) flowmeter can be used to measure retinal blood flow (RBF) parameters, including vessel diameter, blood velocity, and the absolute value of RBF within 2.0 s. We investigated the RBF parameters in eyes with branch retinal vein occlusion (BRVO) using a DOCT flowmeter. METHODS: Seventeen patients with unilateral BRVO were enrolled. All subjects underwent comprehensive ophthalmologic examinations. The RBF parameters were assessed from three veins, i.e., (1) an occluded vein, (2) a non-occluded vein in the BRVO eyes, and (3) an equivalent (superior or inferior) vein in the fellow eye (non-affected vein), using prototype DOCT flowmeter (Topcon, Tokyo, Japan). Moreover, the correlation between RBF parameters and the best corrected visual acuity (BCVA) was examined. We investigated the correlation between (1) the RBF parameters and the time from the initial visit, (2) the RBF parameters and the time from the last injection, and (3) the RBF parameters and the number of anti-vascular endothelial growth factor injections (VEGF). RESULTS: The diameter of the occluded vein (95.9 ± 24.7 µm) was smaller than that of the non-occluded vein (127.9 ± 23.7 µm) and that of the healthy veins (116.4 ± 13.9 µm). The RBF was lower in the occluded veins (4.7 ± 3.7 µL/min) than that in the non-occluded veins (10.3 ± 5.1 µL/min; p < 0.01) and in the fellow eyes (8.6 ± 4.0 µL/min; p = 0.013). In contrast, the blood velocity was not significantly different among the three types of veins. BCVA was correlated with the diameter of the occluded vein (ρ = 0.711, p = 0.001) but not with the RBF and blood velocity. The time from the initial visit, the time from the last injection, and the total number of anti-VEGF injections were not associated with any RBF parameters on the occluded vein. CONCLUSIONS: The RBF was significantly lower in the occluded veins than that in the other veins, and the diameter of the occluded vein was significantly smaller than that of the other veins in patients with BRVO. However, neither the time from the initial visit, nor the time from the last injection, nor the number of anti-VEGF injections were correlated with the RBF parameters on the occluded vein.

[Recurrence-Free Survival after Repeated Resections for Metastatic Inguinal Tumor in Colorectal Mucinous Adenocarcinoma-A Case Report].

A 79-year-old male presented with right inguinal mass and right leg pain. Laparoscopic right hemicolectomy was performed for transverse colon cancer(type 1, muc, pSS, pN1a, pStage Ⅲa)3 years and 6 months ago. We resected the mass located in the spermatic cord and reconstructed it using the Direct Kugel Patch. Histopathological examination revealed mucinous carcinoma and was diagnosed as a metastatic lesion. Local recurrence was detected in the spermatic cord 1 year after resection, and radical inguinal orchiectomy was performed. Six months after the surgery performed for local recurrence, repeated recurrence was detected in the mesh used for reconstruction. Because this recurrence time was short, the patient opted for chemotherapy; however, this resulted in tumor growth, and surgery had to be scheduled. We performed extended resection of the abdominal wall and reconstruction using the fascia lata tensor muscle flap. Although intestinal obstruction, aspiration pneumonia, and skin flap necrosis were observed, the patient was discharged on the 85th postoperative day and remained alive without recurrence for 17 months. Mucinous carcinoma tends to cause local recurrence and requires adequate surgical margin resection. Extended excision should be considered in such cases of repeated local recurrence without distant metastases.

Longitudinal Changes in Retinal Blood Flow in a Feline Retinal Vein Occlusion Model as Measured by Doppler Optical Coherence Tomography and Optical Coherence Tomography Angiography.

Purpose: We aimed to observe longitudinal changes in retinal blood flow (RBF) and structural transformations in capillaries using Doppler optical coherence tomography (DOCT) and optical coherence tomography angiography (OCTA) in a feline retinal blood occlusion (RVO) model. Methods: RVO was induced by argon green laser photocoagulation (PC) in six eyes of six cats. RBF was measured at a first-order retinal artery and vein by a DOCT flowmeter, and structural changes in the capillaries around the occluded vessels (12 × 12 and 3 × 3 mm) were assessed by OCTA before (at baseline); immediately after PC; and on days 1, 4, 7, and 14 thereafter. Systemic and ocular parameters were monitored during the observation period. Results: There were no significant differences in any systemic or ocular parameters before and after PC. Arterial RBF increased significantly on day 1 (160.6 ± 8.6% vs. baseline, P < 0.001) and decreased below baseline after day 1 through 14. Venous RBF decreased immediately after PC (17.4 ± 9.6% vs. baseline, P = 0.001) and then gradually increased afterwards, but did not return to baseline. OCTA showed dilatation of retinal venules immediately after PC to day 1. Collateral vessels began to form on day 4, had matured by day 7, and were pruned on day 14, which formed as mature as normal retinal venule diameters. Conclusions: With increasing arterial RBF within 1 day after inducing RVO, venules gradually expanded to form collateral vessels, suggesting that collateral vessels originate from existing capillary networks, not neovascularization.

[A Case of Boderline Resectable Pancreatic Cancer Curatively Resected after Chemotherapy with Gemcitabine and Nab-Paclitaxel].

Combination therapy containingnab -paclitaxel(nab-PTX)and gemcitabine(GEM)is widely administered for metastatic pancreatic cancer. Recently, this regimen is likely to be applied for treatment in patients with locally advanced disease or for neoadjuvant chemotherapy(NAC)in patients with borderline resectable(BR)pancreatic cancer. We report a case of BR pancreatic cancer in a patient who was eligible for comparison of the imaging findings with the microscopic findings of the resected specimen. A 72-year-old woman was admitted to our hospital with a complaint of jaundice. Enhanced CT showed a 35mm tumor at the head of the pancreas involvingthe portal vein and in contact with the superior mesenteric artery(SMA). After 4 courses of chemotherapy containinga combination of nab-PTX and GEM, the tumor reduced in size, but was still in contact with the portal vein and SMA on imaging. The level of tumor marker CA19-9 was remarkably reduced. Subtotal stomach-preservingpancreaticoduodenectomy with portal vein reconstruction was performed. Macroscopic findings of the cut surface of the resected specimen showed that a white nodule at the pancreas head involved the portal vein and was in contact with the close-cut margin from the SMA; however, microscopic findings revealed that tumor cells had disappeared in the plexus around the SMA. R0 resection was achieved. The histological treatment effect based on Evans' classification and TNM classification were GradeⅡ and pT3N1aM0(pStage ⅡB), respectively. There has been no recurrence 15 months after the surgery. Based on the abovementioned findings, chemotherapy containing a combination of nab-PTX and GEM can be an effective option of NAC for BR-A pancreatic cancer. Even if the tumor is in contact with the SMA on imaging, when the CA19- 9 level is markedly reduced, there is a possibility of achievingR0 surgery.

Retinal blood flow reduction after panretinal photocoagulation in Type 2 diabetes mellitus: Doppler optical coherence tomography flowmeter pilot study.

To use a Doppler optical coherence tomography (DOCT) flowmeter to investigate segmental retinal blood flow (RBF) and sum of the segmental RBFs (SRBF) changes after panretinal photocoagulation (PRP) was used to treat type 2 diabetes mellitus with severe diabetic retinopathy (DR). Data from five patients with proliferative DR (PDR) (mean age 51.9 ± 10.5 years) was analyzed. The vessel diameter (D), average velocity (V), and retinal blood flow (RBF) in veins were measured using a DOCT flowmeter before and four weeks after PRP. Segmental RBF from inferotemporal (IT), superotemporal (ST), inferonasal (IN), and superonasal (SN) veins were measured, and SRBF was defined as the sum of these measurements. All data were analyzed by Wilcoxson test. After PRP, there were statistically significant decreases in the every segmental D, V, RBF (P<0.03) and SRBF (P = 0.002). The other parameters showed no statistically significant differences (P>0.05). The DOCT flowmeter has the potential to be a clinically useful tool to noninvasively evaluate the changes in retinal circulation during PRP in patients with PDR.

Repeatability and Reproducibility of Retinal Blood Flow Measurement Using a Doppler Optical Coherence Tomography Flowmeter in Healthy Subjects.

Purpose: To evaluate the repeatability and reproducibility of retinal blood flow (RBF) measurements in humans by using new auto-alignment and measurement software in a commercially available Doppler optical coherence tomography (DOCT) system. Methods: The DOCT flowmeter assessed the intrasession repeatability and the intersession and interobserver reproducibility of the RBF measurements. For intrasession repeatability, the coefficients of variation (CVs) of five repeated RBF measurements were calculated at the retinal arteries and veins in 20 normal eyes of 20 healthy volunteers. For intersession reproducibility, two sets of three measurements obtained by one observer on 2 different days were compared. For interobserver reproducibility, two sets of three measurements obtained by two observers on the same day were compared. Intraclass correlation coefficients (ICCs) also were used to evaluate the repeatability and reproducibility. The relevance of the DOCT flowmeter and laser Doppler velocimetry (LDV) also was assessed. Results: Regarding intrasession repeatability, the ICC of the RBF exceeded 0.90 in arterioles and venules (ICC: 0.994 and 0.970, respectively). The CVs of the RBF in the arterioles and venules were 6.0% ± 3.4% and 8.8% ± 5.1%, respectively. The intersession and interobserver RBF values had high reproducibility in the arterioles (ICC: 0.980 and 0.993, respectively) and venules (ICC: 0.982 and 0.986, respectively). The RBF measured with the DOCT flowmeter was correlated strongly with LDV in the arterioles (r = 0.76; P < 0.001). Conclusions: The DOCT flowmeter had good reproducibility in the arterioles and venules and precisely measured the RBF as compared to the LDV in the arterioles.

Glial Endothelin-1 Regulates Retinal Blood Flow During Hyperoxia in Cats.

PURPOSE: To investigate the role of endothelin-1 (ET-1) in retinal glial cells in regulating retinal blood flow (RBF) during hyperoxia in cats. METHODS: We measured the vessel diameter (D), blood velocity (V), and blood flow (F) simultaneously in first-order retinal arterioles using a laser Doppler velocimetry system. The animals were under general anesthesia during hyperoxia (100% oxygen) for 10 minutes 24 hours after intravitreal injection of L-2-aminoadipic acid (LAA), a gliotoxic compound, or diluted hydrochloric acid (0.01 N) used as the vehicle control. We also measured the changes in the RBF after intravitreal injection of BQ-123, a specific ET type A receptor antagonist, in LAA-treated eyes. To examine if endothelin-converting enzyme-1 (ECE-1), as an ET-1-generating enzyme located in retinal glial cells, immunohistochemical examinations with costaining of antiglial fibrillary acidic protein (GFAP) antibody and anti-ECE-1 antibody were performed in whole-mount retinas. RESULTS: During hyperoxia, the decreases in D, V, and F in response to hyperoxia were attenuated significantly (P < 0.01 for all comparisons) in the LAA-treated eyes compared with the vehicle control (LAA, D, -8.5 ± 1.5%; V, -13.8 ± 1.5%; F, -27.8 ± 3.0% versus vehicle control, D, -16.8 ± 1.3%; V, -26.3 ± 2.0%; F, -48.9 ± 2.4%). In LAA-treated eyes, intravitreal injections of BQ-123 did not change the rate of hyperoxia-induced RBF compared to LAA-treated eyes. The anti-ECE-1 antibody was costained with anti-GFAP antibody in the whole-mount retinas. CONCLUSIONS: The current findings suggest that retinal glial ET-1 may play an important role in regulating RBF during hyperoxia in cats.

Evaluation of Retinal Circulation Using Segmental-Scanning Doppler Optical Coherence Tomography in Anesthetized Cats.

PURPOSE: To study retinal blood flow (RBF) measurement reproducibility using segmental-scanning Doppler optical coherence tomography (DOCT) in vitro in glass capillaries and in vivo in anesthetized cats. METHODS: As a preliminary study, the flow rates of human blood through glass capillaries were changed by using an infusion pump and measured at 13 preset velocities by DOCT. For in vivo measurement, the cats were anesthetized using sevoflurane. The flow in the parent vessel was compared with the sum of the flow values in the two daughter vessels. The RBF was measured using two different instruments: bidirectional laser Doppler velocimetry (LDV) and DOCT. The reproducibility of the measurements was assessed by calculating the coefficients of variation (CVs) for repeated measurements of RBF at the superior retinal arterioles and venules. RESULTS: In vitro, the flow velocities measured by DOCT agreed well with the preset velocities. In vivo, the flow in the parent vessel agreed with the sum of the flow values in the two daughter vessels. In addition, there were no significant differences in the mean averaged CVs of the RBF in both the arterioles and venules between LDV and DOCT. CONCLUSIONS: The newly developed segmental-scanning DOCT revealed the accuracy of the measurement in in vitro glass capillaries and reproducibility of the measurements of blood velocity in both the retinal arterioles and venules in anesthetized cats.

Mechanism of Developmental Effects in Rats Caused by an N-Phenylimide Herbicide: Transient Fetal Anemia and Sequelae during Mid-to-Late Gestation.

BACKGROUND: Rat developmental toxicity including embryolethality and teratogenicity (mainly ventricular septal defects [VSDs] and wavy ribs) was produced by an N-phenylimide herbicide that inhibits protoporphyrinogen oxidase (PPO) common to chlorophyll and heme biosynthesis. Major characteristics of the developmental toxicity included species difference between rats and rabbits, compound-specific difference among structurally similar herbicides, and sensitive period. Protoporphyrin accumulation in treated fetuses closely correlated with the major characteristics. Iron deposits in erythroblastic mitochondria and degeneration of erythroblasts were observed in treated rat fetuses. In this study we investigated fetal anemia and subsequent developmental effects in rats, and inhibition of PPO in rats, rabbits, and humans by the herbicides in vitro. METHODS: Fetuses were treated on gestational day (GD) 12 and removed on GDs 13 through 20. All litters were examined externally. One half of litters were examined for blood and skeletal development, and the other half for interventricular foramen closure. Effects on PPO were determined in mitochondria from embryos and adult livers. RESULTS: Fetal anemia in rats was evident on GDs 13 through 16. Subsequently, enlarged heart, delayed closure of the foramen, reduced serum protein, and retarded rib ossification were observed. In vitro PPO inhibition exhibited species- and compound-specific differences corresponding to the developmental toxicity. CONCLUSION: We propose that developmental toxicity results from PPO inhibition in primitive erythroblasts, causing transient fetal anemia followed by death. Compensatory enlargement of the fetal heart results in failure of interventricular foramen closure and VSD. Reduced serum protein leads to delayed ossification and wavy ribs.

Role of Glial Cells in Regulating Retinal Blood Flow During Flicker-Induced Hyperemia in Cats.

PURPOSE: To investigate how glial cells participate in retinal circulation during flicker stimulation in cats. METHODS: Using laser Doppler velocimetry, we measured the vessel diameter and blood velocity simultaneously and calculated the retinal blood flow (RBF) in feline first-order retinal arterioles. Twenty-four hours after intravitreal injections of L-2-aminoadipic acid (LAA), a gliotoxic compound, and the solvent of 0.01 N hydrochloric acid as a control, we examined the changes in RBF in response to 16-Hz flicker stimulation for 3 minutes. We also measured the changes in RBF 2 hours after intravitreal injection of Nω-propyl-L-arginine (L-NPA), a selective neuronal nitric oxide synthase inhibitor, in LAA-treated eyes. To evaluate the effects of LAA on retinal neuronal function, ERGs were monitored. Immunohistochemical examinations were performed. RESULTS: In LAA-treated eyes, histologic changes selectively occurred in retinal glial cells. There were no significant reductions in amplitude or elongation of implicit time in ERG after LAA injections compared with controls. In control eyes, the RBF gradually increased and reached the maximal level (53.5% ± 2.5% increase from baseline) after 2 to 3 minutes of flicker stimulation. In LAA-treated eyes, the increases in RBF during flicker stimulation were attenuated significantly compared with controls. In LAA-treated eyes 2 hours after injection of L-NPA, flicker-evoked increases in RBF decreased significantly compared with LAA-treated eyes. CONCLUSIONS: The current results suggested that increases in RBF in response to flicker stimulation were regulated partly by retinal glial cells.

Effect of intravitreal Rho kinase inhibitor ripasudil (K-115) on feline retinal microcirculation.

Ripasudil (K-115) is a novel Rho kinase inhibitor with a potent intraocular pressure-lowering effect. However, it is unclear whether ripasudil affects the retinal blood flow (RBF). We investigated the effect of ripasudil on feline retinal microcirculation. Ripasudil (5 µM, 50 µM or 5 mM; n = 5 each concentration) or vehicle (PBS; n = 5) was injected intravitreally. The vessel diameter (D) and blood velocity (V) were measured by laser Doppler velocimetry simultaneously in the first-order retinal arterioles and the RBF was calculated. The measurements started 5 min before the injection and were performed every 10 min for 120 min. After the intravitreal injection, the retinal circulatory parameters did not change significantly in PBS or 5 µM of ripasudil. The blood V and RBF increased significantly compared to baseline, whereas the vessel D did not change significantly in 50 µM and 5 mM of ripasudil. The V in 50 µM, and the V and RBF in 5 mM of ripasudil significantly increased compared to those in PBS. Intravitreal administration of ripasudil increased the blood V and RBF in cats, suggesting that ripasudil has the potential to improve the retinal blood flow.

Role of neuronal nitric oxide synthase in regulating retinal blood flow during flicker-induced hyperemia in cats.

PURPOSE: To investigate how neuronal nitric oxide synthase (nNOS) contributes to regulation of the retinal circulation during rest and flicker stimulation in cats. METHODS: Using laser Doppler velocimetry, we measured the vessel diameter and blood velocity simultaneously and calculated the retinal blood flow (RBF) in feline first-order retinal arterioles. After intravitreal injections of Nω-Nitro-L-arginine methyl ester (L-NAME), a nonselective NOS inhibitor, and Nω-propyl-L-arginine (L-NPA), a selective nNOS inhibitor, we continuously monitored the retinal circulation without any perturbations for 2 hours. We then examined the changes in the RBF in response to 16-Hz flicker stimuli for 3 minutes at 2 hours after intravitreal injection of phosphate-buffered saline (PBS) as a control, L-NAME, L-NPA, and thromboxane A2 (TXA2) analogue U46619 as a basal tone-adjusted control. RESULTS: After intravitreal injection of L-NAME and L-NPA, the baseline RBF decreased gradually in a dose-dependent manner. In the PBS group, the RBF increased gradually and reached a maximal level after 2 to 3 minutes of flicker stimuli. After 3 minutes of 16-Hz flicker stimuli, the RBF increased by 53.5% ± 3.4% compared with baseline. In the L-NAME and L-NPA groups, the increases in RBF during flicker stimulation were attenuated significantly compared with the PBS group. In the TXA2 group, the reduction in the flicker-induced increase in RBF was comparable to that in the PBS group. CONCLUSIONS: The current results suggested that increased RBF in response to flicker stimulation may be mediated by nitric oxide (NO) production via nNOS activation.

[A Case of Pathologically Complete Response of a Rectal Cancer after Preoperative Treatment with mFOLFOX6 and Radiation Therapy].

A 60-year-old man who had bloody stools after sigmoid colonoscopy was admitted to our hospital. A digital examination and sigmoid colonoscopy showed a type 2 circular tumor at location Rb with incomplete mobility and tumor hemorrhage, and the result of a biopsy was moderately differentiated adenocarcinoma (tub2). Computed tomography and magnetic resonance imaging suggested a possibility of invasion of the primary rectal tumor to the sacrum. The clinical stage was cT4bN0M0H0P0, cStage Ⅱ, which is generally not treatable by surgery. Sigmoid colostomy was performed, and a central venous port was implanted. After a preoperative treatment consisting of 3 courses of mFOLFOX6 and radiation therapy, the clinical stage changed to ycT2N0M0H0P0, ycStageⅠ. Super-low anterior resection and covering ileostomy were performed 46 days after the preoperative treatment. A pathological examination revealed no residual cancer cells in the primary lesion and lymph node (Grade 3, pCR). The patient has been disease-free for 4 years and 9 months after the operation.